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Basal ganglia–hippocampal interactions support the role of the hippocampal formation in sensorimotor integration
Experimental Neurology 188 (2004) 430 – 443 www.elsevier.com/locate/yexnr
Basal ganglia–hippocampal interactions support the role of the hippocampal formation in sensorimotor integration Nicholas E. Hallworth and Brian H. Bland * Department of Psychology, Behavioral Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada T2N 1N4 Received 3 February 2004; revised 5 April 2004; accepted 19 April 2004 Available online 28 May 2004
Abstract Experiments were carried out to evaluate whether neural activity in the basal ganglia is functionally related to the neural activity underlying mechanisms of theta band oscillation and synchrony in the hippocampal formation. Experiment 1 demonstrated that electrical stimulation administered to the substantia nigra, globus pallidus (GP) and caudate-putamen (CPu) in urethane anesthetized rats elicited theta field activity in the hippocampal formation. Subsequent microinfusion of the local anesthetic procaine hydrochloride into the medial septum reversibly abolished this effect. In Experiment 2, single cell discharge profiles established for 152 cells recorded in nuclei of the basal ganglia resulted in 101 (66%) being classified as theta-related and 51 (34%) classified as nonrelated. Theta-related cells were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF (n = 22). Tonic theta-ON and tonic theta-OFF cells displayed irregular or regular (tonic) discharge patterns. Rhythmic discharge patterns did not occur in any theta-related cells in the nuclei of the basal ganglia. However, analyses using Kaneoke and Vitek’s [J. Neurosci. Methods 68, (1996) 211] algorithms revealed that 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns whereas 27/51 (53%) of the nonrelated cells displayed periodicity in their discharge patterns. The periodicities in the majority of cells were in frequency ranges above that of theta band oscillation and synchrony. The results support the following conclusions: (1) the cellular activity of the basal ganglia, composed of nuclei traditionally associated with motor functions, is functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the observed functional connectivity provides support for the role of the hippocampal formation in sensorimotor integration. D 2004 Elsevier Inc. All rights reserved. Keywords: Substantia nigra; Caudate-putamen; Globus pallidus; Hippocampus; Theta; Single units; EEG
Introduction The basal ganglia consist of many nuclei that participate in the control of movement, specifically the initiation of internally generated movements and the regulation and monitoring of ongoing movements (Cote and Crutcher, 1991; Wise et al., 1996). Albin et al. (1989) formulated a unifying model of the functional organization of the basal ganglia. This model, expanded and elaborated by other groups (reviewed by Smith et al., 1998), is based on ‘‘direct’’ and ‘‘indirect’’ pathways of cortical and thalamic information flow through the basal ganglia. The two output nuclei of the basal ganglia, the internal pallidal segment
* Corresponding author. Behavioral Neuroscience Research Group, Department of Psychology, University of Calgary, 2500 University Drive, NW, Calgary, Alberta, Canada T2N 1N4. E-mail address: [email protected] (B.H. Bland). 0014-4886/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2004.04.014
[enteropeduncular nucleus (EP) in the rat] and the substantia nigra pars reticulata (SNR) provide continuous levels of inhibition to target cells in the thalamus and brainstem. This inhibitory output is modulated by two parallel pathways, one direct and one indirect. In the direct pathway, information passes from the striatum [caudate and putamen (CPu)] directly to the output nuclei [globus pallidus (GP), EP and SNR]. The indirect pathway passes first to the external pallidal segment (GP in the rat), through to the subthalamic nucleus (STN) and then to the output nuclei. Bland and Oddie (2001) recently reviewed data supporting the case that theta band oscillation and synchrony is involved in mechanisms underlying sensorimotor integration (Bland, 1986). According to this model, neural circuitry underlying the production of oscillation and synchrony (theta) in limbic cortex and associated structures functions in the capacity of providing voluntary motor systems with continually updated feedback on their performance relative to changing environmental (sensory) conditions. A crucial
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aspect of this performance is the intensity with which the motor programs are initiated and maintained. The ascending brainstem hippocampal synchronizing pathways make the primary contribution in this regard. These pathways originate in rostral pontine nuclei, the reticularis pontis oralis (RPO) and pedunculopontine tegmental nucleus (PPT), ascend and synapse with nuclei in the caudal diencephalon, the posterior hypothalamic nucleus (PH) and supramammillary nucleus (SUM), which in turn send projections to the medial septal nucleus and nucleus of the vertical limb of the diagonal band of Broca (MS/vDBB) (Bland and Oddie, 1998; Vertes and Kocsis, 1997). The medial septum functions as the node of the ascending synchronizing pathways, relaying inputs to the hippocampal formation, cingulate cortex and entorhinal cortex (Bland, 2000). In the updated version of the sensorimotor integration model, the posterior hypothalamus is assigned the major role of relaying movement-related information from motor systems to the hippocampal formation, via the medial septum. The model thus predicts relationships between the neural activity underlying theta band oscillation and synchrony in the hippocampal formation (and related structures) and the neural activity in motor structures such as the basal ganglia. Recent data (Caplan et al., 2003) on human theta oscillations recorded during a virtual maze task have provided support for the sensorimotor integration model. Anatomically, there are many connections by which nuclei of the basal ganglia may interact either directly with the hippocampal formation or indirectly via the ascending brainstem hippocampal synchronizing pathways. Mogenson et al. (1980) provided support for the idea that the nucleus accumbens functions as an interface between the limbic system and motor structures, such as the basal ganglia, translating motivation to action. Evidence for a hippocampal-accumbens-substantia nigra pathway was also reviewed by Lopes da Silva et al. (1985). Groenewegen et al. (1987) provided evidence for hippocampal output fibers traveling via the subiculum to parts of the striatum whereas McGeorge and Faull (1989) demonstrated connections from the entorhinal cortex to the striatum. Finally, the caudateputamen, globus pallidus, subthalamic nucleus and the substation nigra share reciprocal connections with the PPT, allowing interactions between the basal ganglia and the ascending brainstem hippocampal synchronizing pathways (Bevan and Bolam, 1995; Fortin, 1995; Spann and Grofova, 1989). The purpose of the present paper was to evaluate the hypothesis that neural activity of the basal ganglia is functionally related to the neural activity underlying mechanisms of theta band oscillation and synchrony in the hippocampal formation. Three experimental procedures were carried out to achieve this objective: (1) nuclei of the basal ganglia were stimulated electrically to determine if this could elicit theta field activity in the hippocampal formation; (2) if electrical stimulation of a given basal ganglia nucleus elicited hippocampal theta field activity, procaine
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hydrochloride was then microinfused into the medial septum to ascertain whether the synchronizing effects were mediated via this node of the ascending brainstem synchronizing pathways; (3) single cell discharge activity in nuclei of the basal ganglia was recorded during hippocampal field states of synchrony (theta) and asynchrony (large amplitude irregular activity—LIA). Cell discharges were analyzed according to the theta-related classification system of Colom and Bland (1987) and by the burst and Lomb periodogram algorithms of Kaneoke and Vitek (1996). Portions of this research have been reported previously in abstract form (Hallworth and Bland, 1999).
Materials and methods Subjects and surgical procedures The data were obtained from 105 male Long –Evans strain black-hooded rats (0.125 –0.150 kg) obtained from the Animal Care Services at the University of Calgary. The rats were initially anesthetized with a mixture of halothane (M.T.C. Pharmaceuticals) in oxygen 1.5 vol.% (minimum alveolar concentration) while a jugular cannula was inserted. The rats were then switched to urethane (ethyl carbamate) gradually administered via the cannula until a total injection of 0.8 g/kg was achieved, with subsequent titrated doses given if necessary to maintain an adequate level of anesthesia during the remaining surgical and experimental procedures. Following insertion of a tracheal cannula, rats were secured in a stereotaxic apparatus. The rat’s core body temperature was maintained at 37jC (Harvard Instruments heating pad), and heart rate was monitored constantly throughout the experiment. Rats were prepared for stereotaxic surgery in the standard manner. The plane between bregma and lambda was leveled to horizontal and bregma was used as a reference point for the stereotaxic coordinates. An uninsulated tungsten wire, placed in the cortex anterior to bregma, served as an indifferent electrode, and the stereotaxic frame was connected to ground. A tungsten reference microelectrode (0.2 –0.5 MV) for recording hippocampal field activity was implanted in the molecular layer of the dentate gyrus (3.3 mm posterior, 2.2 mm lateral to bregma and 2.8 mm ventral to the dural surface). In experiment 1, the coordinates for placement of the stimulating electrodes were: substantia nigra, 5.4 mm posterior to bregma, 2.4 mm lateral and 7.1 – 8.4 mm ventral from dural surface; globus pallidus, 1.3 mm posterior to bregma, 3.1 –3.7 mm lateral and 4.8 – 7.5 mm ventral to dural surface; caudate-putamen, 1.7 mm anterior to bregma, 0.8 mm posterior to bregma, 3.0 – 4.2 mm lateral and 3.2 to 6.8, 7.0 or 7.6 mm ventral to dural surface, with the deeper depths corresponding to more posterior coordinates. The coordinates for microinfusion into the medial septum were 0.5 mm anterior to bregma, 0.0 mm lateral and 5.5 mm ventral to the dural surface. In
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experiment 2, the coordinates for cell recordings were: substantia nigra, 5.4 mm posterior to bregma, 2.4 mm lateral. Cells in the substantia nigra pars compacta were recorded at depths between 6.7 and 7.1 mm ventral from dural surface. Cells in the substantia nigra pars reticulata were recorded at depths between 7.1 –8.4 mm ventral from dural surface; globus pallidus, 1.3 mm posterior to bregma, 3.1 – 3.7 mm lateral. Cells in the globus pallidus were recorded at depths between 4.8 and 7.5 mm ventral to dural surface; caudate-putamen, 1.7 mm anterior to bregma, 0.8 mm posterior to bregma, 3.0 –4.2 mm lateral. Cells in the caudate-putamen (CPu) were recorded at depths ranging from 3.2 to 6.8, 7.0 or 7.6 mm ventral to dural surface, with the deeper depths corresponding to more posterior coordinates. Shank length of the microelectrodes was 10.0 mm resulting in negligible compression of the brain during recording. Electrode tip locations were marked by passing 50 AA of current for 15 min (5 min cathodal, 5 min anodal, 5 min cathodal). Following perfusion and fixation of the brain, frozen sections (30 Am) were taken serially and mounted on glass slides for subsequent verification of HPC field and cell recording sites.
were amplified and displayed, then stored on FM tape for further off-line analysis. Signals were led into two Grass model P511 preamplifiers. One preamplifier isolated field activity, which was led into a model 7D Grass polygraph with filter settings of 1 and 35 Hz and the unit preamplifier was set at 300 Hz to 3 kHz. From these preamplifiers, the field and cell signals were led to a 55100 series Tektronix oscilloscope and the TEAC cassette recorder. Additionally, signals passing out of the cell preamplifiers were led into a Grass AM5 audio monitor. Cells were recorded using glass microelectrodes filled with 0.5 M sodium acetate mixed with 2% Pontamine sky blue (5– 8 MV). The procedures for cell recording in experiment 2 were the following: once a cell was isolated with a satisfactory signal to noise ratio, the cell was observed on line for a minimum of 5 min and if no change occurred in the signal to noise ratio, the cell was considered stable. A minimum of 20 min of cell discharges along with the simultaneously occurring hippocampal field were recorded, ensuring that approximately equal samples of LIA and theta were collected. If not enough spontaneous theta occurred, light tail pinches were administered. Upon completion of the recording protocol, the staining protocol was initiated.
Stimulating, microinfusion, and recording procedures Data analysis Bipolar stimulating electrodes were constructed with insulated stainless steel wire (Driver-Harris, 0.01 diameter) and connected to miniature male Winchester pins. Electrical stimulation was carried out using a photoelectric stimulus isolation unit for constant current output (current range setting of 1– 1.5 mA), with stimulation intensity controlled by the voltage output of the stimulator. Stimulation pulses were biphasic with duration of 0.1 ms and a frequency of 100 Hz. Procaine hydrochloride (20% by volume) was infused into the medial septum at a flow rate of 0.5 Al/ min. A 23-gauge tube served as a guide for a 30-gauge injection stillette connected to an infusion pump via a 10Al gas-tight syringe. The stimulation procedure (n = 9) in experiment 1 was the following: once the stimulating electrode was placed, a stimulus train was administered for 10 s at an intensity of 0.2 mA. If this failed to elicit theta, current was increased in 0.05 mA steps either until reliable theta field activity was elicited or until a maximum of 0.6 mA was reached. A minimum of four 10-s samples of stimulation was collected, along with a minimum of two trials where a light tail pinch was administered to elicit theta field activity. The microinfusion procedure was as follows: In four animals, once the electrical stimulation procedure was carried out, a dose of 1 Al of 20% procaine was microinfused into the medial septum at a flow rate of 0.5 Al/min., and the same pre-drug protocol of electrical stimulation and tail pinch trials were administered. Between 30 and 60 min of recovery from the effects of procaine microinfusion, the entire protocol was again repeated. During recording, brain signals of hippocampal field and single cell discharges recorded in the basal ganglia nuclei
Data segments were analyzed using a PC microcomputer and acquisition and analysis software (Data Wave Technologies, Longmount, CO). Hippocampal field activity was sampled at 133 Hz and cell activity at 16 kHz. In experiment 1, three 5-s samples of field data for each of the pre-procaine stimulation trials, procaine stimulation trials and post-procaine stimulation trials were subjected to fast Fourier transform (FFT). Theta field activity was defined as a sinusoidal-like waveform with a narrow band peak frequency of 3 –12 Hz. In experiment 2, three 5-s samples of field data for each of the conditions of spontaneously occurring theta-, LIA- and tail pinch induced theta field activity, and the accompanying cell discharges, were analyzed. In addition to the definition of the theta field state, LIA was defined as large amplitude irregular activity with a broad 0.5 –25 Hz frequency range. Data Wave software provided the mean, standard error of the mean and the range of cell discharges. Based on these analyses, theta-related cells were classified as theta-ON or theta-OFF (Colom and Bland, 1987) according to discharge rates during the HPC field states (assessed statistically with paired t tests, accepted significance at P < 0.05), with subclassifications as phasic if the cells were rhythmically discharging and phase-related to the HPC theta field, or tonic if the cells discharged in a regular or irregular nonrhythmic pattern. Cells that did not fit these criteria were considered nonrelated. Software provided by Kaneoke and Vitek (1996) allowed the computing of density, autocorrelation (AC) and interspike interval histograms as well as Lomb periodograms of the digitized cell discharges (see Fig. 1). Finally, the relationship between cell discharges and the
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Fig. 1. Analyses for characterization of cell discharge patterns. (Upper portion) Representative unit activity (200-ms duration) recorded from a neuron classified as periodic. This cell discharged in a regular pattern with an approximately 32-ms interspike interval. (Bottom portion) Analyses used to classify the cell as periodic. Discharge density and AC histograms and Lomb periodograms were provided by Kaneoke and Vitek’s (1996) analysis software and the ISI histograms were provided by Data Wave software.
accompanying field activity was assessed by computing cross-correlation functions (CCF) using a frequency domain algorithm (Press et al., 1992).
Results Experiment 1 Electrical stimulation of the SN elicited hippocampal theta field activity in eight experiments with the stimulating electrode located contralateral to the hippocampus and in one experiment with the stimulating electrode located ipsilateral to the hippocampus. Of the nine stimulating sites, one was in the SNC, six were in the middle region of the SNR and two were in the lateral portion of the SNR. In four of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the SN. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all four cases. Fig. 2 shows a representative example of one of the SN stimulating and medial septal microinfusion experiments. Electrical stimulation of the GP elicited hippocampal theta field activity in six experiments with the stimulating electrode located contralateral to the hippocampus and in one experiment with the stimulating electrode located ipsilateral to the hippocampus. One stimulation site failed
to elicit theta. Subsequent histological analyses revealed that all seven stimulation sites capable of eliciting theta were in the GP although the site that failed to do so was in the ventral posteromedial thalamic nucleus. In three of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the GP. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all three cases. Fig. 3 shows a representative example of one of the GP stimulating and medial septal microinfusion experiments. Electrical stimulation of the CPu elicited hippocampal theta field activity in 10 experiments with the stimulating electrode located contralateral to the hippocampus. Histological analyses revealed that nine of the stimulating electrodes were in the middle of the CPu relative to the anteroposterior and dorsoventral extent of the nucleus. One electrode was located more medially in the CPu, close to the wall of the lateral ventricle. In three of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the CPu. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all three cases. Fig. 4 shows a
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Fig. 2. Hippocampal field activity in response to electrical stimulation of the substantia nigra, before (top panel), during (third panel) and 1 h after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
representative example of one of the CPu stimulating and medial septal microinfusion experiments. Experiment 2 General results for all basal ganglia cells Cell discharge profiles were established for 152 cells recorded in nuclei of the basal ganglia and of these 101
(66%) were classified as theta-related and 51 (34%) were classified as nonrelated. Theta-related cells were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF (n = 22). Tonic theta-ON cells displayed irregular or regular nonbursting discharge patterns. That is, analyses using Kaneoke and Vitek’s (1996) algorithms revealed that 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns whereas 27/51 (53%) of the non-
Fig. 3. Hippocampal field activity in response to electrical stimulation of the globus pallidus, before (top panel), during (third panel) and 45 min after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
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Fig. 4. Hippocampal field activity in response to electrical stimulation of the caudate-putamen, before (top panel), during (third panel) and 40 min after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
related cells displayed periodicity in their discharge patterns (see Table 1 for summary). CCF analyses revealed there were no significant relationships between hippocampal field activity and the discharges of theta-related cells in the basal ganglia. A small percentage of these cells exhibited very weak CCFs with RHO values in the range of F0.2. Of the 152 cells recorded, a total of 70 cell recording sites were found by successfully locating Pontamine Sky Blue dots in the histological sections. The remaining 82 cell recording sites were determined by electrode tract localization and depth measurements relative to Pontamine markings. Globus pallidus cells Theta-related classifications Forty-five cells were recorded in the GP. Of the 45 cells, 30 were classified as theta-related and 15 were classified as
Table 1 Summary of the total number of cells recorded in the basal ganglia nuclei and their classification along the theta-related and periodic dimensions Cell location
Theta cell classification
Periodicity Periodic
Nonperiodic
Substantia nigra (45)
ON (15) OFF (9) nonrelated (21) ON (28) OFF (2) nonrelated (15) ON (36) OFF (11) nonrelated (15)
12 5 18 9 0 3 20 5 6
3 4 3 19 2 12 16 6 9
Globus pallidus (45)
Caudate-putamen (62)
nonrelated. Theta-related cells were subclassified as tonic theta-ON (n = 28, mean and standard deviation of firing rates during theta, 17.09 F 1.6 Hz, and 2.34 F 0.06 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 2, mean and standard deviation of firing rates during theta 2.8 F 0.40 Hz, and 10.00 F 0.93 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 7.3 F 0.74 Hz and 5.1 F 0.6 Hz, respectively (not significantly different). Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 9/28 tonic theta-ON cells recorded in the GP (mean periodicity = 17.09 F 1.62 Hz) and 3/15 nonrelated cells (mean periodicity = 3.17 F 0.46 Hz). The two theta-OFF cells recorded were both classified as nonperiodic. Examples of representative discharge patterns related to theta and LIA for all tonic theta-ON nonperiodic cells recorded in the GP are shown in Fig. 5. The figure shows the cell discharge pattern accompanying the transition from LIAto tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 6. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 5. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinchinduced theta had principal frequency components of 3.4 and 4.2 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed was 3.4 F 0.0 Hz and that of all tail pinch-induced theta trails was 4.0 F 0.3 Hz. The analyses for determining the periodicity of the cell
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LIA condition was due to an insufficient number of cell discharges. The CCF obtained for the spontaneous theta trials were not significant whereas those of the tail pinchinduced theta trials revealed a moderate cross-correlation, with a discharge preference for the positive portion of the theta waves. Substantia nigra cells
Fig. 5. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a globus pallidus cell classified as tonic thetaON nonperiodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
discharges are shown in columns 2 and 3. The lack of periodicity shown in the AC histogram for all trials is confirmed by the lack of significant peaks in the Lomb periodograms. The last column shows the CCFs calculated for the cell and field activity in each of the field conditions. The flat line in the CCF function calculated for the
Theta-related classifications Forty-five cells were recorded in the SN (15 in the SNC and 30 in the SNR). Of the 45 cells, 24 were classified as theta-related and 21 were classified as nonrelated, with the proportions of each category approximately equal in the two divisions of the SN. Theta-related cells were subclassified as tonic theta-ON (n = 15, mean and standard deviation of firing rates during theta, 24.6 F 1.1 Hz, and 15.3 F 0.4 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 9, mean and standard deviation of firing rates during theta 6.0 F 0.43 Hz, and 8.4 F 0.42 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 15.1 F 0.53 and 14.0 F 0.37 Hz, respectively (not significantly different).
Fig. 6. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the globus pallidus cell shown in Fig. 5. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Fig. 7. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a substantia nigra cell classified as nonrelated periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 12/15 tonic theta-ON cells (mean periodicity = 24.6 F 1.05 Hz), 5/9 tonic theta-OFF cells (mean periodicity = 8.37 F 0.42 Hz) and 18/21 nonrelated cells (mean periodicity = 7.51 F 0.32 Hz), with the remaining cells in each category
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classified as nonperiodic. Significant peaks in the Lomb periodograms of theta-related cells were not consistently associated with the occurrence of theta field activity, occurring equally as often during LIA field activity. Examples of representative discharge patterns related to theta and LIA for all nonrelated periodic cells recorded in the SNR are shown in Fig. 7. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 8. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 7. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.4 and 4.2 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed was 3.4 F 0.0 Hz and that of all tail pinchinduced theta trails was 4.0 F 0.2 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The periodicity shown in the AC histogram for all trials is confirmed by the significant peaks ( P = 0.00074 for LIA trial, at a frequency of 7.6 Hz, P < 0.00016 for the spontaneous theta trial, at a frequency of 8.1 Hz, and P < 0.018 for the tail pinch trial, at a frequency of 9.1 Hz) in the Lomb periodograms. The last column shows
Fig. 8. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the substantia nigra cell shown in Fig. 7. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Caudate-putamen cells
Fig. 9. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a caudate-putamen cell classified as tonic theta-ON periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
the CCFs calculated for the cell and field activity in each of the field conditions, revealing there were no significant relationships.
Theta-related classifications Sixty-two cells were recorded in the CPu and of these, 47 were classified as theta-related and 15 were classified as nonrelated. Theta-related cells were subclassified as tonic theta-ON (n = 36, mean and standard deviation of firing rates during theta, 16.2 F 0.97 Hz, and 8.8 F 0.41 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 11, mean and standard deviation of firing rates during theta 5.4 F 0.71 Hz, and 12.8 F 0.65 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 14.46 F 0.66 and 13.29 F 0.54 Hz, respectively (not significantly different). Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 20/36 tonic theta-ON cells (mean periodicity = 16.22 F 0.98 Hz), 5/11 tonic theta-OFF cells (mean periodicity = 12.75 F 0.65 Hz) and 6/15 nonrelated cells (mean periodicity = 25.50 F 0.73 Hz), with the remaining cells in each category classified as nonperiodic. Examples of representa-
Fig. 10. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the caudate-putamen cell shown in Fig. 9. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Fig. 11. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a caudate-putamen cell classified as tonic theta-OFF periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
tive discharge patterns related to theta and LIA for all tonic theta-ON periodic cells recorded in the CPu are shown in Fig. 9. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 10. The first column on the
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left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 9. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.4 and 4.4 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed for this cell was 3.5 F 0.3 Hz and that of all tail pinch-induced theta trails was 4.6 F 0.3 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The AC histograms for all LIA trials did not show any peaks and the lack of periodicity was confirmed by the nonsignificant Lomb periodograms. The AC histograms for the spontaneous theta trials revealed some very weak peaks but they did not achieve significance in the Lomb periodogram analysis. The AC histograms for all tail pinch-induced theta trials revealed stronger peaks and this periodicity was confirmed by the significant peak ( P = 0.024) in the Lomb periodogram at a frequency of 19.5 Hz. The last column shows the CCFs calculated for the cell and field activity in each of the field conditions, revealing there were no significant relationships. Examples of representative discharge patterns related to theta and LIA for all tonic theta-OFF periodic cells recorded
Fig. 12. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the caudate-putamen cell shown in Fig. 11. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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in the CPu are shown in Fig. 11. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 12. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 10. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.6 and 4.2 Hz, respectively. The mean principal frequency for this cell over all spontaneous trials analyzed was 3.2 F 0.8 Hz and that of all tail pinch-induced theta trails was 4.2 F 0.0 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The AC histograms for all LIA trials revealed peaks and this periodicity was confirmed by the significant Lomb periodograms ( P < 0.00014, at a frequency of 28.7 Hz for the example provided). The AC histograms for the spontaneous theta and tail pinch-induced theta trials revealed some very weak peaks but they did not achieve significance in the Lomb periodogram analysis. The last column shows the CCFs calculated for the cell and field activity in the LIA and spontaneous theta field conditions, revealing there were no significant relationships. A moderate relationship was revealed for the tail pinch-induced theta trails, with a cell discharge preference shown for the negative phase of the theta waves.
Discussion In Experiment 1, electrical stimulation of the substantia nigra, globus pallidus and caudate-putamen reliably induced theta field activity in the hippocampal formation. The microinfusion of the local anesthetic procaine hydrochloride into the medial septum rendered this stimulation temporarily ineffective. The findings in the present paper corroborate the earlier findings of Sabatino et al. (1985, 1986, 1989) who demonstrated that electrical stimulation of basal ganglia nuclei elicited theta field activity in the hippocampus of cats. These authors also showed that electrical lesions of the medial septum abolished the theta induced by stimulation of caudate-putamen and the substantia nigra pars compacta. The data from the electrical stimulation and procaine microinfusion studies support two conclusions: (1) nuclei of the basal ganglia are functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the generation of hippocampal theta field activity elicited by electrical stimulation of basal ganglia nuclei occurs via a septohippocampal pathway, similar to theta elicited by electrical stimulation of other nuclei of the ascending brainstem hippocampal synchronizing pathways. Future work is needed to clarify the pathways by which the basal ganglia nuclei interact with the ascending brainstem hippocampal synchronizing pathways.
In Experiment 2, the cell discharge profiles established for 152 cells recorded in nuclei of the basal ganglia during synchronous (theta) and asynchronous (LIA) hippocampal field activity conditions revealed that 101 (66%) of the cells were theta-related, whereas the remaining 51 (34%) cells were nonrelated. This is the first work we are aware of, which investigates theta-related cells in the basal ganglia. Distinct theta-ON and theta-OFF populations of cells were first described in acute preparations using extracellular recordings by Colom et al. (1987), followed by a detailed cell classification paper by Colom and Bland (1987) and subsequently used to classify theta-related cells in the HPC in many studies (Bland and Colom, 1988, 1989; Bland et al., 1996; Colom et al., 1991; Konopacki et al., 1992; Mizumori et al., 1990; Smythe et al., 1991). Theta-ON and theta-OFF cells have also been recorded in the medial septal nucleus and nucleus of the diagonal band of Broca (MS/vDBB) (Bland et al., 1990, 1994; Colom and Bland, 1991; Ford et al., 1989), the entorhinal cortex (Dickson et al., 1994, 1995), cingulate cortex (Colom et al., 1988), caudal diencephalon (Bland et al., 1995; Kirk et al., 1996), rostral pontine region (Hanada et al., 1999), the superior colliculus (Natsume et al., 1999), the red nucleus (Dypvik and Bland, personal communication) and the neocortex (Lukatch and MacIver, 1997). The theta-related cells in the present study were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF cells (n = 22). All cells recorded in the basal ganglia discharged in irregular or regular (tonic) discharge patterns, during both theta and LIA field conditions. The description of discharge patterns of basal ganglia cells as single spiking or bursting in previous studies has varied depending on the species studied, whether anesthesia was used, the type of anesthetic used and the type of analysis employed. In their pioneering work on substantia nigra cells, using awake, locally anesthetized, immobilized rats, Wilson et al. (1977) described two patterns: (1) irregular cells that could undergo a ‘‘regularization’’ process with increases in firing rate, and (2) bursting cells in both the SNC and the SNR, with twice as many of these in the SNR. Other studies such as that of Gulley et al. (1999) did not report the presence of burst firing in the SNR of freely moving rats. Magill et al. (2000) showed that in rats under ketamine anesthesia, cells in the globus pallidus exhibited bursting, regular or irregular discharge patterns. However, in rats studied under urethane anesthesia, all globus pallidus cells discharged single spikes in a regular manner, similar to the findings of the present study. Wilson (1993) noted that cells in the caudate-putamen were generally classified as having either tonic or bursting discharge patterns, but again, there are discrepancies in the literature as to the relative proportions of each. Additional results from experiment 2, using Kaneoke and Vitek’s (1996) algorithms, revealed that 78/152 (51%) of all cells recorded in the basal ganglia displayed periodicity in their discharge patterns whereas 74/152 (48%) were non-
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periodic. Interestingly, these proportions are very similar to the proportions of periodic theta-related and nonrelated cells, as 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns and 27/51 (53%) of the nonrelated cells displayed periodicity in their discharge patterns. Of the three basal ganglia nuclei investigated, the globus pallidus was observed to have the lowest percentage of cells (27%) displaying periodicities in their discharge patterns. As bursting activity was not detected in any cell discharges by Kaneoke and Vitek’s (1996) algorithms, the periodicity revealed by the Lomb periodogram analyses was near the frequency of the cell’s discharge rate. Since the periodicities for the majority of cells were in frequency ranges well above theta frequency ranges occurring spontaneously in urethane anesthetized rats, the periodic properties of basal ganglia cells were unlikely related to hippocampal theta band oscillation and synchrony. This conclusion was also supported by the observations that periodicity was observed during both hippocampal theta and LIA field conditions, in both thetarelated and nonrelated cell populations. Previous studies have demonstrated that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. Multisecond oscillations in firing rate with periods in the range of 2 –60 s, and averaging 20 –35 s, are present in 50 – 90% of spike trains from neurons in basal ganglia nuclei recorded from locally anesthetized, immobilized rats. Consistent with the findings in the present paper, general anesthesia virtually eliminates them (Allers et al., 2000a,b; Ruskin et al., 1999). Interestingly, Allers et al. (2002) recently demonstrated that multisecond periodicities in basal ganglia firing rates correlated with theta bursts in the transcortical and hippocampal EEG in awake rats. Penttonen et al. (1999) have also demonstrated ultra-slow (0.025 Hz) periodicities in the hippocampus of freely moving rats. Together with the results from experiment 1, the results from experiment 2 provide further support for several conclusions: (1) cells in the substantia nigra, globus pallidus and caudateputamen nuclei of the basal ganglia, traditionally associated with motor functions, are functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the periodicities demonstrated in a significant number of basal ganglia cells are unlikely to be related to the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation for two reasons: they were outside the frequency band of theta and were present in both theta-related and nonrelated basal ganglia cells. In their updated sensorimotor integration model, Bland and Oddie (2001) suggested that activity of the ascending brainstem synchronizing pathways provides the hippocampus with sensory information relevant to the initiation of voluntary movement. This information is relayed from the hippocampus to motor structures (such as the nuclei of the basal ganglia), which in addition to initiating movements send inputs to the posterior hypothalamus signaling that
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these movements have been initiated. As movement continues, the combination of sensory- and movement-related inputs ascend back to the hippocampus, allowing the hippocampus to integrate sensory and motor information necessary for the initiation and maintenance of voluntary motor behavior. The anatomical location of the basal ganglia nuclei and their functional properties is ideally suited to provide both the necessary sensory inputs to the hippocampus for signaling movement initiation and the movementrelated inputs for their maintenance, via the ascending brainstem synchronizing pathways. In summary, the results of the present study provide support for the sensorimotor integration model of hippocampal function (Bland and Oddie, 2001) since the model predicted functional relationships between the neural activity underlying theta band oscillation and synchrony in the hippocampal formation (and related structures) and the neural activity in motor structures such as the basal ganglia.
Acknowledgments This work was supported by Natural Sciences and Engineering Research Council of Canada Grant A9935 to B.H. Bland and a Neuroscience Canada Foundation Award to N. E. Hallworth. We would also like to thank Stephen Glasgow for editorial work and insightful discussion on the manuscript.
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Basal ganglia–hippocampal interactions support the role of the hippocampal formation in sensorimotor integration Nicholas E. Hallworth and Brian H. Bland * Department of Psychology, Behavioral Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada T2N 1N4 Received 3 February 2004; revised 5 April 2004; accepted 19 April 2004 Available online 28 May 2004
Abstract Experiments were carried out to evaluate whether neural activity in the basal ganglia is functionally related to the neural activity underlying mechanisms of theta band oscillation and synchrony in the hippocampal formation. Experiment 1 demonstrated that electrical stimulation administered to the substantia nigra, globus pallidus (GP) and caudate-putamen (CPu) in urethane anesthetized rats elicited theta field activity in the hippocampal formation. Subsequent microinfusion of the local anesthetic procaine hydrochloride into the medial septum reversibly abolished this effect. In Experiment 2, single cell discharge profiles established for 152 cells recorded in nuclei of the basal ganglia resulted in 101 (66%) being classified as theta-related and 51 (34%) classified as nonrelated. Theta-related cells were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF (n = 22). Tonic theta-ON and tonic theta-OFF cells displayed irregular or regular (tonic) discharge patterns. Rhythmic discharge patterns did not occur in any theta-related cells in the nuclei of the basal ganglia. However, analyses using Kaneoke and Vitek’s [J. Neurosci. Methods 68, (1996) 211] algorithms revealed that 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns whereas 27/51 (53%) of the nonrelated cells displayed periodicity in their discharge patterns. The periodicities in the majority of cells were in frequency ranges above that of theta band oscillation and synchrony. The results support the following conclusions: (1) the cellular activity of the basal ganglia, composed of nuclei traditionally associated with motor functions, is functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the observed functional connectivity provides support for the role of the hippocampal formation in sensorimotor integration. D 2004 Elsevier Inc. All rights reserved. Keywords: Substantia nigra; Caudate-putamen; Globus pallidus; Hippocampus; Theta; Single units; EEG
Introduction The basal ganglia consist of many nuclei that participate in the control of movement, specifically the initiation of internally generated movements and the regulation and monitoring of ongoing movements (Cote and Crutcher, 1991; Wise et al., 1996). Albin et al. (1989) formulated a unifying model of the functional organization of the basal ganglia. This model, expanded and elaborated by other groups (reviewed by Smith et al., 1998), is based on ‘‘direct’’ and ‘‘indirect’’ pathways of cortical and thalamic information flow through the basal ganglia. The two output nuclei of the basal ganglia, the internal pallidal segment
* Corresponding author. Behavioral Neuroscience Research Group, Department of Psychology, University of Calgary, 2500 University Drive, NW, Calgary, Alberta, Canada T2N 1N4. E-mail address: [email protected] (B.H. Bland). 0014-4886/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2004.04.014
[enteropeduncular nucleus (EP) in the rat] and the substantia nigra pars reticulata (SNR) provide continuous levels of inhibition to target cells in the thalamus and brainstem. This inhibitory output is modulated by two parallel pathways, one direct and one indirect. In the direct pathway, information passes from the striatum [caudate and putamen (CPu)] directly to the output nuclei [globus pallidus (GP), EP and SNR]. The indirect pathway passes first to the external pallidal segment (GP in the rat), through to the subthalamic nucleus (STN) and then to the output nuclei. Bland and Oddie (2001) recently reviewed data supporting the case that theta band oscillation and synchrony is involved in mechanisms underlying sensorimotor integration (Bland, 1986). According to this model, neural circuitry underlying the production of oscillation and synchrony (theta) in limbic cortex and associated structures functions in the capacity of providing voluntary motor systems with continually updated feedback on their performance relative to changing environmental (sensory) conditions. A crucial
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aspect of this performance is the intensity with which the motor programs are initiated and maintained. The ascending brainstem hippocampal synchronizing pathways make the primary contribution in this regard. These pathways originate in rostral pontine nuclei, the reticularis pontis oralis (RPO) and pedunculopontine tegmental nucleus (PPT), ascend and synapse with nuclei in the caudal diencephalon, the posterior hypothalamic nucleus (PH) and supramammillary nucleus (SUM), which in turn send projections to the medial septal nucleus and nucleus of the vertical limb of the diagonal band of Broca (MS/vDBB) (Bland and Oddie, 1998; Vertes and Kocsis, 1997). The medial septum functions as the node of the ascending synchronizing pathways, relaying inputs to the hippocampal formation, cingulate cortex and entorhinal cortex (Bland, 2000). In the updated version of the sensorimotor integration model, the posterior hypothalamus is assigned the major role of relaying movement-related information from motor systems to the hippocampal formation, via the medial septum. The model thus predicts relationships between the neural activity underlying theta band oscillation and synchrony in the hippocampal formation (and related structures) and the neural activity in motor structures such as the basal ganglia. Recent data (Caplan et al., 2003) on human theta oscillations recorded during a virtual maze task have provided support for the sensorimotor integration model. Anatomically, there are many connections by which nuclei of the basal ganglia may interact either directly with the hippocampal formation or indirectly via the ascending brainstem hippocampal synchronizing pathways. Mogenson et al. (1980) provided support for the idea that the nucleus accumbens functions as an interface between the limbic system and motor structures, such as the basal ganglia, translating motivation to action. Evidence for a hippocampal-accumbens-substantia nigra pathway was also reviewed by Lopes da Silva et al. (1985). Groenewegen et al. (1987) provided evidence for hippocampal output fibers traveling via the subiculum to parts of the striatum whereas McGeorge and Faull (1989) demonstrated connections from the entorhinal cortex to the striatum. Finally, the caudateputamen, globus pallidus, subthalamic nucleus and the substation nigra share reciprocal connections with the PPT, allowing interactions between the basal ganglia and the ascending brainstem hippocampal synchronizing pathways (Bevan and Bolam, 1995; Fortin, 1995; Spann and Grofova, 1989). The purpose of the present paper was to evaluate the hypothesis that neural activity of the basal ganglia is functionally related to the neural activity underlying mechanisms of theta band oscillation and synchrony in the hippocampal formation. Three experimental procedures were carried out to achieve this objective: (1) nuclei of the basal ganglia were stimulated electrically to determine if this could elicit theta field activity in the hippocampal formation; (2) if electrical stimulation of a given basal ganglia nucleus elicited hippocampal theta field activity, procaine
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hydrochloride was then microinfused into the medial septum to ascertain whether the synchronizing effects were mediated via this node of the ascending brainstem synchronizing pathways; (3) single cell discharge activity in nuclei of the basal ganglia was recorded during hippocampal field states of synchrony (theta) and asynchrony (large amplitude irregular activity—LIA). Cell discharges were analyzed according to the theta-related classification system of Colom and Bland (1987) and by the burst and Lomb periodogram algorithms of Kaneoke and Vitek (1996). Portions of this research have been reported previously in abstract form (Hallworth and Bland, 1999).
Materials and methods Subjects and surgical procedures The data were obtained from 105 male Long –Evans strain black-hooded rats (0.125 –0.150 kg) obtained from the Animal Care Services at the University of Calgary. The rats were initially anesthetized with a mixture of halothane (M.T.C. Pharmaceuticals) in oxygen 1.5 vol.% (minimum alveolar concentration) while a jugular cannula was inserted. The rats were then switched to urethane (ethyl carbamate) gradually administered via the cannula until a total injection of 0.8 g/kg was achieved, with subsequent titrated doses given if necessary to maintain an adequate level of anesthesia during the remaining surgical and experimental procedures. Following insertion of a tracheal cannula, rats were secured in a stereotaxic apparatus. The rat’s core body temperature was maintained at 37jC (Harvard Instruments heating pad), and heart rate was monitored constantly throughout the experiment. Rats were prepared for stereotaxic surgery in the standard manner. The plane between bregma and lambda was leveled to horizontal and bregma was used as a reference point for the stereotaxic coordinates. An uninsulated tungsten wire, placed in the cortex anterior to bregma, served as an indifferent electrode, and the stereotaxic frame was connected to ground. A tungsten reference microelectrode (0.2 –0.5 MV) for recording hippocampal field activity was implanted in the molecular layer of the dentate gyrus (3.3 mm posterior, 2.2 mm lateral to bregma and 2.8 mm ventral to the dural surface). In experiment 1, the coordinates for placement of the stimulating electrodes were: substantia nigra, 5.4 mm posterior to bregma, 2.4 mm lateral and 7.1 – 8.4 mm ventral from dural surface; globus pallidus, 1.3 mm posterior to bregma, 3.1 –3.7 mm lateral and 4.8 – 7.5 mm ventral to dural surface; caudate-putamen, 1.7 mm anterior to bregma, 0.8 mm posterior to bregma, 3.0 – 4.2 mm lateral and 3.2 to 6.8, 7.0 or 7.6 mm ventral to dural surface, with the deeper depths corresponding to more posterior coordinates. The coordinates for microinfusion into the medial septum were 0.5 mm anterior to bregma, 0.0 mm lateral and 5.5 mm ventral to the dural surface. In
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experiment 2, the coordinates for cell recordings were: substantia nigra, 5.4 mm posterior to bregma, 2.4 mm lateral. Cells in the substantia nigra pars compacta were recorded at depths between 6.7 and 7.1 mm ventral from dural surface. Cells in the substantia nigra pars reticulata were recorded at depths between 7.1 –8.4 mm ventral from dural surface; globus pallidus, 1.3 mm posterior to bregma, 3.1 – 3.7 mm lateral. Cells in the globus pallidus were recorded at depths between 4.8 and 7.5 mm ventral to dural surface; caudate-putamen, 1.7 mm anterior to bregma, 0.8 mm posterior to bregma, 3.0 –4.2 mm lateral. Cells in the caudate-putamen (CPu) were recorded at depths ranging from 3.2 to 6.8, 7.0 or 7.6 mm ventral to dural surface, with the deeper depths corresponding to more posterior coordinates. Shank length of the microelectrodes was 10.0 mm resulting in negligible compression of the brain during recording. Electrode tip locations were marked by passing 50 AA of current for 15 min (5 min cathodal, 5 min anodal, 5 min cathodal). Following perfusion and fixation of the brain, frozen sections (30 Am) were taken serially and mounted on glass slides for subsequent verification of HPC field and cell recording sites.
were amplified and displayed, then stored on FM tape for further off-line analysis. Signals were led into two Grass model P511 preamplifiers. One preamplifier isolated field activity, which was led into a model 7D Grass polygraph with filter settings of 1 and 35 Hz and the unit preamplifier was set at 300 Hz to 3 kHz. From these preamplifiers, the field and cell signals were led to a 55100 series Tektronix oscilloscope and the TEAC cassette recorder. Additionally, signals passing out of the cell preamplifiers were led into a Grass AM5 audio monitor. Cells were recorded using glass microelectrodes filled with 0.5 M sodium acetate mixed with 2% Pontamine sky blue (5– 8 MV). The procedures for cell recording in experiment 2 were the following: once a cell was isolated with a satisfactory signal to noise ratio, the cell was observed on line for a minimum of 5 min and if no change occurred in the signal to noise ratio, the cell was considered stable. A minimum of 20 min of cell discharges along with the simultaneously occurring hippocampal field were recorded, ensuring that approximately equal samples of LIA and theta were collected. If not enough spontaneous theta occurred, light tail pinches were administered. Upon completion of the recording protocol, the staining protocol was initiated.
Stimulating, microinfusion, and recording procedures Data analysis Bipolar stimulating electrodes were constructed with insulated stainless steel wire (Driver-Harris, 0.01 diameter) and connected to miniature male Winchester pins. Electrical stimulation was carried out using a photoelectric stimulus isolation unit for constant current output (current range setting of 1– 1.5 mA), with stimulation intensity controlled by the voltage output of the stimulator. Stimulation pulses were biphasic with duration of 0.1 ms and a frequency of 100 Hz. Procaine hydrochloride (20% by volume) was infused into the medial septum at a flow rate of 0.5 Al/ min. A 23-gauge tube served as a guide for a 30-gauge injection stillette connected to an infusion pump via a 10Al gas-tight syringe. The stimulation procedure (n = 9) in experiment 1 was the following: once the stimulating electrode was placed, a stimulus train was administered for 10 s at an intensity of 0.2 mA. If this failed to elicit theta, current was increased in 0.05 mA steps either until reliable theta field activity was elicited or until a maximum of 0.6 mA was reached. A minimum of four 10-s samples of stimulation was collected, along with a minimum of two trials where a light tail pinch was administered to elicit theta field activity. The microinfusion procedure was as follows: In four animals, once the electrical stimulation procedure was carried out, a dose of 1 Al of 20% procaine was microinfused into the medial septum at a flow rate of 0.5 Al/min., and the same pre-drug protocol of electrical stimulation and tail pinch trials were administered. Between 30 and 60 min of recovery from the effects of procaine microinfusion, the entire protocol was again repeated. During recording, brain signals of hippocampal field and single cell discharges recorded in the basal ganglia nuclei
Data segments were analyzed using a PC microcomputer and acquisition and analysis software (Data Wave Technologies, Longmount, CO). Hippocampal field activity was sampled at 133 Hz and cell activity at 16 kHz. In experiment 1, three 5-s samples of field data for each of the pre-procaine stimulation trials, procaine stimulation trials and post-procaine stimulation trials were subjected to fast Fourier transform (FFT). Theta field activity was defined as a sinusoidal-like waveform with a narrow band peak frequency of 3 –12 Hz. In experiment 2, three 5-s samples of field data for each of the conditions of spontaneously occurring theta-, LIA- and tail pinch induced theta field activity, and the accompanying cell discharges, were analyzed. In addition to the definition of the theta field state, LIA was defined as large amplitude irregular activity with a broad 0.5 –25 Hz frequency range. Data Wave software provided the mean, standard error of the mean and the range of cell discharges. Based on these analyses, theta-related cells were classified as theta-ON or theta-OFF (Colom and Bland, 1987) according to discharge rates during the HPC field states (assessed statistically with paired t tests, accepted significance at P < 0.05), with subclassifications as phasic if the cells were rhythmically discharging and phase-related to the HPC theta field, or tonic if the cells discharged in a regular or irregular nonrhythmic pattern. Cells that did not fit these criteria were considered nonrelated. Software provided by Kaneoke and Vitek (1996) allowed the computing of density, autocorrelation (AC) and interspike interval histograms as well as Lomb periodograms of the digitized cell discharges (see Fig. 1). Finally, the relationship between cell discharges and the
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Fig. 1. Analyses for characterization of cell discharge patterns. (Upper portion) Representative unit activity (200-ms duration) recorded from a neuron classified as periodic. This cell discharged in a regular pattern with an approximately 32-ms interspike interval. (Bottom portion) Analyses used to classify the cell as periodic. Discharge density and AC histograms and Lomb periodograms were provided by Kaneoke and Vitek’s (1996) analysis software and the ISI histograms were provided by Data Wave software.
accompanying field activity was assessed by computing cross-correlation functions (CCF) using a frequency domain algorithm (Press et al., 1992).
Results Experiment 1 Electrical stimulation of the SN elicited hippocampal theta field activity in eight experiments with the stimulating electrode located contralateral to the hippocampus and in one experiment with the stimulating electrode located ipsilateral to the hippocampus. Of the nine stimulating sites, one was in the SNC, six were in the middle region of the SNR and two were in the lateral portion of the SNR. In four of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the SN. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all four cases. Fig. 2 shows a representative example of one of the SN stimulating and medial septal microinfusion experiments. Electrical stimulation of the GP elicited hippocampal theta field activity in six experiments with the stimulating electrode located contralateral to the hippocampus and in one experiment with the stimulating electrode located ipsilateral to the hippocampus. One stimulation site failed
to elicit theta. Subsequent histological analyses revealed that all seven stimulation sites capable of eliciting theta were in the GP although the site that failed to do so was in the ventral posteromedial thalamic nucleus. In three of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the GP. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all three cases. Fig. 3 shows a representative example of one of the GP stimulating and medial septal microinfusion experiments. Electrical stimulation of the CPu elicited hippocampal theta field activity in 10 experiments with the stimulating electrode located contralateral to the hippocampus. Histological analyses revealed that nine of the stimulating electrodes were in the middle of the CPu relative to the anteroposterior and dorsoventral extent of the nucleus. One electrode was located more medially in the CPu, close to the wall of the lateral ventricle. In three of these experiments, procaine was microinfused into the medial septum resulting in the total abolishment of theta field activity in response to both a tail pinch and electrical stimulation of the CPu. In all experiments, theta field activity returned in response to tail pinch and electrical stimulation between 40 and 60 min following the infusion of procaine. Histology revealed the accurate location of the microinfusion cannula within the medial septum in all three cases. Fig. 4 shows a
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Fig. 2. Hippocampal field activity in response to electrical stimulation of the substantia nigra, before (top panel), during (third panel) and 1 h after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
representative example of one of the CPu stimulating and medial septal microinfusion experiments. Experiment 2 General results for all basal ganglia cells Cell discharge profiles were established for 152 cells recorded in nuclei of the basal ganglia and of these 101
(66%) were classified as theta-related and 51 (34%) were classified as nonrelated. Theta-related cells were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF (n = 22). Tonic theta-ON cells displayed irregular or regular nonbursting discharge patterns. That is, analyses using Kaneoke and Vitek’s (1996) algorithms revealed that 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns whereas 27/51 (53%) of the non-
Fig. 3. Hippocampal field activity in response to electrical stimulation of the globus pallidus, before (top panel), during (third panel) and 45 min after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
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Fig. 4. Hippocampal field activity in response to electrical stimulation of the caudate-putamen, before (top panel), during (third panel) and 40 min after (bottom panel) procaine-induced inactivation of the medial septum. In addition, a tail pinch is shown (second panel) during the inactivation period. Solid bars indicate the duration of the applied stimulus conditions.
related cells displayed periodicity in their discharge patterns (see Table 1 for summary). CCF analyses revealed there were no significant relationships between hippocampal field activity and the discharges of theta-related cells in the basal ganglia. A small percentage of these cells exhibited very weak CCFs with RHO values in the range of F0.2. Of the 152 cells recorded, a total of 70 cell recording sites were found by successfully locating Pontamine Sky Blue dots in the histological sections. The remaining 82 cell recording sites were determined by electrode tract localization and depth measurements relative to Pontamine markings. Globus pallidus cells Theta-related classifications Forty-five cells were recorded in the GP. Of the 45 cells, 30 were classified as theta-related and 15 were classified as
Table 1 Summary of the total number of cells recorded in the basal ganglia nuclei and their classification along the theta-related and periodic dimensions Cell location
Theta cell classification
Periodicity Periodic
Nonperiodic
Substantia nigra (45)
ON (15) OFF (9) nonrelated (21) ON (28) OFF (2) nonrelated (15) ON (36) OFF (11) nonrelated (15)
12 5 18 9 0 3 20 5 6
3 4 3 19 2 12 16 6 9
Globus pallidus (45)
Caudate-putamen (62)
nonrelated. Theta-related cells were subclassified as tonic theta-ON (n = 28, mean and standard deviation of firing rates during theta, 17.09 F 1.6 Hz, and 2.34 F 0.06 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 2, mean and standard deviation of firing rates during theta 2.8 F 0.40 Hz, and 10.00 F 0.93 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 7.3 F 0.74 Hz and 5.1 F 0.6 Hz, respectively (not significantly different). Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 9/28 tonic theta-ON cells recorded in the GP (mean periodicity = 17.09 F 1.62 Hz) and 3/15 nonrelated cells (mean periodicity = 3.17 F 0.46 Hz). The two theta-OFF cells recorded were both classified as nonperiodic. Examples of representative discharge patterns related to theta and LIA for all tonic theta-ON nonperiodic cells recorded in the GP are shown in Fig. 5. The figure shows the cell discharge pattern accompanying the transition from LIAto tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 6. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 5. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinchinduced theta had principal frequency components of 3.4 and 4.2 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed was 3.4 F 0.0 Hz and that of all tail pinch-induced theta trails was 4.0 F 0.3 Hz. The analyses for determining the periodicity of the cell
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LIA condition was due to an insufficient number of cell discharges. The CCF obtained for the spontaneous theta trials were not significant whereas those of the tail pinchinduced theta trials revealed a moderate cross-correlation, with a discharge preference for the positive portion of the theta waves. Substantia nigra cells
Fig. 5. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a globus pallidus cell classified as tonic thetaON nonperiodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
discharges are shown in columns 2 and 3. The lack of periodicity shown in the AC histogram for all trials is confirmed by the lack of significant peaks in the Lomb periodograms. The last column shows the CCFs calculated for the cell and field activity in each of the field conditions. The flat line in the CCF function calculated for the
Theta-related classifications Forty-five cells were recorded in the SN (15 in the SNC and 30 in the SNR). Of the 45 cells, 24 were classified as theta-related and 21 were classified as nonrelated, with the proportions of each category approximately equal in the two divisions of the SN. Theta-related cells were subclassified as tonic theta-ON (n = 15, mean and standard deviation of firing rates during theta, 24.6 F 1.1 Hz, and 15.3 F 0.4 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 9, mean and standard deviation of firing rates during theta 6.0 F 0.43 Hz, and 8.4 F 0.42 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 15.1 F 0.53 and 14.0 F 0.37 Hz, respectively (not significantly different).
Fig. 6. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the globus pallidus cell shown in Fig. 5. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Fig. 7. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a substantia nigra cell classified as nonrelated periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 12/15 tonic theta-ON cells (mean periodicity = 24.6 F 1.05 Hz), 5/9 tonic theta-OFF cells (mean periodicity = 8.37 F 0.42 Hz) and 18/21 nonrelated cells (mean periodicity = 7.51 F 0.32 Hz), with the remaining cells in each category
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classified as nonperiodic. Significant peaks in the Lomb periodograms of theta-related cells were not consistently associated with the occurrence of theta field activity, occurring equally as often during LIA field activity. Examples of representative discharge patterns related to theta and LIA for all nonrelated periodic cells recorded in the SNR are shown in Fig. 7. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 8. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 7. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.4 and 4.2 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed was 3.4 F 0.0 Hz and that of all tail pinchinduced theta trails was 4.0 F 0.2 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The periodicity shown in the AC histogram for all trials is confirmed by the significant peaks ( P = 0.00074 for LIA trial, at a frequency of 7.6 Hz, P < 0.00016 for the spontaneous theta trial, at a frequency of 8.1 Hz, and P < 0.018 for the tail pinch trial, at a frequency of 9.1 Hz) in the Lomb periodograms. The last column shows
Fig. 8. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the substantia nigra cell shown in Fig. 7. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Caudate-putamen cells
Fig. 9. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a caudate-putamen cell classified as tonic theta-ON periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
the CCFs calculated for the cell and field activity in each of the field conditions, revealing there were no significant relationships.
Theta-related classifications Sixty-two cells were recorded in the CPu and of these, 47 were classified as theta-related and 15 were classified as nonrelated. Theta-related cells were subclassified as tonic theta-ON (n = 36, mean and standard deviation of firing rates during theta, 16.2 F 0.97 Hz, and 8.8 F 0.41 Hz during LIA, significantly different at P < 0.05) and tonic theta-OFF (n = 11, mean and standard deviation of firing rates during theta 5.4 F 0.71 Hz, and 12.8 F 0.65 Hz during LIA, significantly different at P < 0.05). Firing rates during theta and LIA for nonrelated cells were 14.46 F 0.66 and 13.29 F 0.54 Hz, respectively (not significantly different). Burst and periodicity analyses Significant peaks in the Lomb periodograms were found in 20/36 tonic theta-ON cells (mean periodicity = 16.22 F 0.98 Hz), 5/11 tonic theta-OFF cells (mean periodicity = 12.75 F 0.65 Hz) and 6/15 nonrelated cells (mean periodicity = 25.50 F 0.73 Hz), with the remaining cells in each category classified as nonperiodic. Examples of representa-
Fig. 10. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the caudate-putamen cell shown in Fig. 9. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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Fig. 11. Relationships between asynchronous (LIA) hippocampal field activity and tail pinch-induced synchronous (theta) hippocampal field activity and the discharges of a caudate-putamen cell classified as tonic theta-OFF periodic. The upper trace is the hippocampal field activity recorded from the molecular layer of the dentate region, and the lower trace is the discharge pattern of the cell accompanying these field conditions. The figure illustrates a tail pinch-induced LIA – theta transition.
tive discharge patterns related to theta and LIA for all tonic theta-ON periodic cells recorded in the CPu are shown in Fig. 9. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 10. The first column on the
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left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 9. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.4 and 4.4 Hz, respectively. The mean principal frequency over all spontaneous trials analyzed for this cell was 3.5 F 0.3 Hz and that of all tail pinch-induced theta trails was 4.6 F 0.3 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The AC histograms for all LIA trials did not show any peaks and the lack of periodicity was confirmed by the nonsignificant Lomb periodograms. The AC histograms for the spontaneous theta trials revealed some very weak peaks but they did not achieve significance in the Lomb periodogram analysis. The AC histograms for all tail pinch-induced theta trials revealed stronger peaks and this periodicity was confirmed by the significant peak ( P = 0.024) in the Lomb periodogram at a frequency of 19.5 Hz. The last column shows the CCFs calculated for the cell and field activity in each of the field conditions, revealing there were no significant relationships. Examples of representative discharge patterns related to theta and LIA for all tonic theta-OFF periodic cells recorded
Fig. 12. Analysis of the data segments for each of the three hippocampal field conditions and accompanying discharges of the caudate-putamen cell shown in Fig. 11. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions, the second column the autocorrelation histogram (AC), the third column the Lomb periodogram and the fourth column the cross-correlation function (CCF). Details in text.
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in the CPu are shown in Fig. 11. The figure shows the cell discharge pattern accompanying the transition from LIA- to tail pinch-induced theta field activity. The analysis of the data segments for the three field conditions is shown in Fig. 12. The first column on the left shows the results of the FFT analysis for each of the hippocampal field conditions shown in Fig. 10. The analysis of LIA shows the lack of a peak frequency whereas spontaneous theta- and tail pinch-induced theta had principal frequency components of 3.6 and 4.2 Hz, respectively. The mean principal frequency for this cell over all spontaneous trials analyzed was 3.2 F 0.8 Hz and that of all tail pinch-induced theta trails was 4.2 F 0.0 Hz. The analyses for determining the periodicity of the cell discharges are shown in columns 2 and 3. The AC histograms for all LIA trials revealed peaks and this periodicity was confirmed by the significant Lomb periodograms ( P < 0.00014, at a frequency of 28.7 Hz for the example provided). The AC histograms for the spontaneous theta and tail pinch-induced theta trials revealed some very weak peaks but they did not achieve significance in the Lomb periodogram analysis. The last column shows the CCFs calculated for the cell and field activity in the LIA and spontaneous theta field conditions, revealing there were no significant relationships. A moderate relationship was revealed for the tail pinch-induced theta trails, with a cell discharge preference shown for the negative phase of the theta waves.
Discussion In Experiment 1, electrical stimulation of the substantia nigra, globus pallidus and caudate-putamen reliably induced theta field activity in the hippocampal formation. The microinfusion of the local anesthetic procaine hydrochloride into the medial septum rendered this stimulation temporarily ineffective. The findings in the present paper corroborate the earlier findings of Sabatino et al. (1985, 1986, 1989) who demonstrated that electrical stimulation of basal ganglia nuclei elicited theta field activity in the hippocampus of cats. These authors also showed that electrical lesions of the medial septum abolished the theta induced by stimulation of caudate-putamen and the substantia nigra pars compacta. The data from the electrical stimulation and procaine microinfusion studies support two conclusions: (1) nuclei of the basal ganglia are functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the generation of hippocampal theta field activity elicited by electrical stimulation of basal ganglia nuclei occurs via a septohippocampal pathway, similar to theta elicited by electrical stimulation of other nuclei of the ascending brainstem hippocampal synchronizing pathways. Future work is needed to clarify the pathways by which the basal ganglia nuclei interact with the ascending brainstem hippocampal synchronizing pathways.
In Experiment 2, the cell discharge profiles established for 152 cells recorded in nuclei of the basal ganglia during synchronous (theta) and asynchronous (LIA) hippocampal field activity conditions revealed that 101 (66%) of the cells were theta-related, whereas the remaining 51 (34%) cells were nonrelated. This is the first work we are aware of, which investigates theta-related cells in the basal ganglia. Distinct theta-ON and theta-OFF populations of cells were first described in acute preparations using extracellular recordings by Colom et al. (1987), followed by a detailed cell classification paper by Colom and Bland (1987) and subsequently used to classify theta-related cells in the HPC in many studies (Bland and Colom, 1988, 1989; Bland et al., 1996; Colom et al., 1991; Konopacki et al., 1992; Mizumori et al., 1990; Smythe et al., 1991). Theta-ON and theta-OFF cells have also been recorded in the medial septal nucleus and nucleus of the diagonal band of Broca (MS/vDBB) (Bland et al., 1990, 1994; Colom and Bland, 1991; Ford et al., 1989), the entorhinal cortex (Dickson et al., 1994, 1995), cingulate cortex (Colom et al., 1988), caudal diencephalon (Bland et al., 1995; Kirk et al., 1996), rostral pontine region (Hanada et al., 1999), the superior colliculus (Natsume et al., 1999), the red nucleus (Dypvik and Bland, personal communication) and the neocortex (Lukatch and MacIver, 1997). The theta-related cells in the present study were further subclassified as tonic theta-ON cells (n = 79) and tonic theta-OFF cells (n = 22). All cells recorded in the basal ganglia discharged in irregular or regular (tonic) discharge patterns, during both theta and LIA field conditions. The description of discharge patterns of basal ganglia cells as single spiking or bursting in previous studies has varied depending on the species studied, whether anesthesia was used, the type of anesthetic used and the type of analysis employed. In their pioneering work on substantia nigra cells, using awake, locally anesthetized, immobilized rats, Wilson et al. (1977) described two patterns: (1) irregular cells that could undergo a ‘‘regularization’’ process with increases in firing rate, and (2) bursting cells in both the SNC and the SNR, with twice as many of these in the SNR. Other studies such as that of Gulley et al. (1999) did not report the presence of burst firing in the SNR of freely moving rats. Magill et al. (2000) showed that in rats under ketamine anesthesia, cells in the globus pallidus exhibited bursting, regular or irregular discharge patterns. However, in rats studied under urethane anesthesia, all globus pallidus cells discharged single spikes in a regular manner, similar to the findings of the present study. Wilson (1993) noted that cells in the caudate-putamen were generally classified as having either tonic or bursting discharge patterns, but again, there are discrepancies in the literature as to the relative proportions of each. Additional results from experiment 2, using Kaneoke and Vitek’s (1996) algorithms, revealed that 78/152 (51%) of all cells recorded in the basal ganglia displayed periodicity in their discharge patterns whereas 74/152 (48%) were non-
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periodic. Interestingly, these proportions are very similar to the proportions of periodic theta-related and nonrelated cells, as 51/101 (50%) theta-related cells displayed periodicity in their discharge patterns and 27/51 (53%) of the nonrelated cells displayed periodicity in their discharge patterns. Of the three basal ganglia nuclei investigated, the globus pallidus was observed to have the lowest percentage of cells (27%) displaying periodicities in their discharge patterns. As bursting activity was not detected in any cell discharges by Kaneoke and Vitek’s (1996) algorithms, the periodicity revealed by the Lomb periodogram analyses was near the frequency of the cell’s discharge rate. Since the periodicities for the majority of cells were in frequency ranges well above theta frequency ranges occurring spontaneously in urethane anesthetized rats, the periodic properties of basal ganglia cells were unlikely related to hippocampal theta band oscillation and synchrony. This conclusion was also supported by the observations that periodicity was observed during both hippocampal theta and LIA field conditions, in both thetarelated and nonrelated cell populations. Previous studies have demonstrated that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. Multisecond oscillations in firing rate with periods in the range of 2 –60 s, and averaging 20 –35 s, are present in 50 – 90% of spike trains from neurons in basal ganglia nuclei recorded from locally anesthetized, immobilized rats. Consistent with the findings in the present paper, general anesthesia virtually eliminates them (Allers et al., 2000a,b; Ruskin et al., 1999). Interestingly, Allers et al. (2002) recently demonstrated that multisecond periodicities in basal ganglia firing rates correlated with theta bursts in the transcortical and hippocampal EEG in awake rats. Penttonen et al. (1999) have also demonstrated ultra-slow (0.025 Hz) periodicities in the hippocampus of freely moving rats. Together with the results from experiment 1, the results from experiment 2 provide further support for several conclusions: (1) cells in the substantia nigra, globus pallidus and caudateputamen nuclei of the basal ganglia, traditionally associated with motor functions, are functionally connected with the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation; (2) the periodicities demonstrated in a significant number of basal ganglia cells are unlikely to be related to the neural circuitry involved in the generation of theta band oscillation and synchrony in the hippocampal formation for two reasons: they were outside the frequency band of theta and were present in both theta-related and nonrelated basal ganglia cells. In their updated sensorimotor integration model, Bland and Oddie (2001) suggested that activity of the ascending brainstem synchronizing pathways provides the hippocampus with sensory information relevant to the initiation of voluntary movement. This information is relayed from the hippocampus to motor structures (such as the nuclei of the basal ganglia), which in addition to initiating movements send inputs to the posterior hypothalamus signaling that
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these movements have been initiated. As movement continues, the combination of sensory- and movement-related inputs ascend back to the hippocampus, allowing the hippocampus to integrate sensory and motor information necessary for the initiation and maintenance of voluntary motor behavior. The anatomical location of the basal ganglia nuclei and their functional properties is ideally suited to provide both the necessary sensory inputs to the hippocampus for signaling movement initiation and the movementrelated inputs for their maintenance, via the ascending brainstem synchronizing pathways. In summary, the results of the present study provide support for the sensorimotor integration model of hippocampal function (Bland and Oddie, 2001) since the model predicted functional relationships between the neural activity underlying theta band oscillation and synchrony in the hippocampal formation (and related structures) and the neural activity in motor structures such as the basal ganglia.
Acknowledgments This work was supported by Natural Sciences and Engineering Research Council of Canada Grant A9935 to B.H. Bland and a Neuroscience Canada Foundation Award to N. E. Hallworth. We would also like to thank Stephen Glasgow for editorial work and insightful discussion on the manuscript.
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