Neural processing of auditory signals in the time domain: Delay-tuned coincidence detectors in the mustached bat

Hearing Research 324 (2015) 19e36

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Review

Neural processing of auditory signals in the time domain: Delay-tuned coincidence detectors in the mustached bat Nobuo Suga* Department of Biology, Washington University, One Brookings Drive, St. Louis, MO 63130, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 October 2014 Received in revised form 15 February 2015 Accepted 24 February 2015 Available online 6 March 2015

The central auditory system produces combination-sensitive neurons tuned to a specific combination of multiple signal elements. Some of these neurons act as coincidence detectors with delay lines for the extraction of spectro-temporal information from sounds. “Delay-tuned” neurons of mustached bats are tuned to a combination of up to four signal elements with a specific delay between them and form a delay map. They are produced in the inferior colliculus by the coincidence of the rebound response following glycinergic inhibition to the first harmonic of a biosonar pulse with the short-latency response to the 2nde4th harmonics of its echo. Compared with collicular delay-tuned neurons, thalamic and cortical ones respond more to pulse-echo pairs than individual sounds. Cortical delay-tuned neurons are clustered in the three separate areas. They interact with each other through a circuit mediating positive feedback and lateral inhibition for adjustment and improvement of the delay tuning of cortical and subcortical neurons. The current article reviews the mechanisms for delay tuning and the response properties of collicular, thalamic and cortical delay-tuned neurons in relation to hierarchical signal processing. © 2015 Elsevier B.V. All rights reserved.

1. Introduction The central auditory system contains many different types of neurons that preferentially or specifically respond to a certain type of sound. Neurons responding specifically to either tone bursts, FM sounds or noise bursts have been reported since the mid-1960s in different species of animals (e.g., in bats, Suga, 1965b, 1968, 1969; O'Neill, 1985; Fuzessery, 1994), and those responding to speciesspecific complex sounds have been reported since the mid-1970s in frogs (e.g., Mudry et al., 1977; Fuzessery and Feng, 1983), birds (e.g., Leppelsack, 1978; Margoliash, 1983; Margoliash and Fortune, 1992), bats (e.g., Feng et al., 1978; Suga et al., 1978, 1983; O'Neill and Suga, 1979; Schuller et al., 1991) and monkeys (e.g.,

Abbreviations: CF, constant frequency; CF1e4, 1ste4th harmonics of CF signal; dB, decibels; DF, dorsal fringe; E, echo; FF, frequency modulationefrequency modulation; FI, facilitation index; FM, frequency modulation; FM1e4, 1ste4th harmonics of FM signal; FMn, 2nde4th harmonics of echo FM signal; GABA, gammaaminobutyric acid; H1e4, 1ste4th harmonics; N1, summated auditory nerve response; NMDA, N-methyl-D-aspartate; P, pulse; r, correlation coefficient; SPL, sound pressure level; VF, ventral fringe * Tel.: þ1 314 725 0031. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.heares.2015.02.008 0378-5955/© 2015 Elsevier B.V. All rights reserved.

Rauschecker et al., 1995; Brosch et al., 1999; Sadagopan and Wang, 2009). Furthermore, “computational” maps have been found such as the maps for systematic representation of sound amplitudes (Suga, 1977; Suga and Manabe, 1982), echo delays (Suga and O'Neill, 1979; Suga and Horikawa, 1986) or Doppler shifts (Suga et al., 1983) in the auditory cortex of the mustached bat. The echo-delay map is formed by “delay-tuned” combination-sensitive neurons that are tuned to a specific spectrotemporal pattern of sound. Therefore, the exploration of the neural mechanisms underling the response properties of delay-tuned neurons has been an important subject in auditory neurophysiology. By 1990, several reviews had been written, focusing only on the most basic response properties of cortical and thalamic delay-tuned neurons (e.g., Suga, 1990). Since then several important findings have been made about delay-tuned neurons in the cortex, thalamus and then colliculus. It is time to review the progress in the research on those neurons. The author will review the neural mechanisms for delay tuning and the response properties of collicular, thalamic and cortical delay-tuned neurons in relation to hierarchical signal processing, avoiding an overlap with the review articles written by Wenstrup and Portfors (2011) and Wenstrup et al. (2012). Delay-tuned neurons have been studied in different species of bats such as the mustached bat, Pteronotus parnellii (Suga et al.,

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1983; Wenstrup and Portfors, 2011), the big brown bat, Eptesicus fuscus (Feng et al., 1978; Dear et al., 1993), the little brown bat, Myotis lucifugus (Wong and Shannon, 1988; Sullivan, 1982; Wong et al., 1992), and the short-tailed fruit bat, Carollia perspicillata (Hagemann et al., 2010, 2011). Delay-tuned neurons have been much more extensively studied in the mustached bat than in any other species of animals. Therefore, the current article will focus on the data obtained from this species. 2. Coincidence detectors with delay lines The basic response properties of delay-tuned and durationtuned neurons are based upon delay lines, coincidence detection and amplification (facilitation). Delay lines can be produced by conduction delay of action potentials (spikes), synaptic delay, inhibition and membrane properties of post-synaptic neurons. In addition, there are frequency-dependent cochlear delays. Inhibition followed by rebound excitation has various durations. Delaytuned neurons in bats are tuned to specific echo delays. The duration of inhibition acting as delay lines for echo delay tuning is up to 24-ms long in the mustached bat (Suga and O'Neill, 1979), as explained in Section 5. Duration-tuned neurons are tuned to specific durations of acoustic signals such as bio-sonar signals and communication calls. The duration of inhibition acting as delay lines for duration tuning is up to 20-ms long in the big brown bat (Pinheiro et al., 1991) and up to 80-ms long in the mouse (Brand et al., 2000). Overlap of the rebound excitation with an offresponse at the end of an acoustic signal leads to duration tuning. Delay lines produced in the inferior colliculus are due to glycinergic and/or GABAergic inhibition for delay tuning (Nataraj and Wenstrup, 2005) and also for duration tuning (Casseday et al., 1994, 2000; Fuzessery and Hall, 1999; Jen and Feng, 1999; Jen and Wu, 2005). There are two major categories of coincidence detectors with delay lines: those associated with presynaptic neurons that have identical frequency tuning and those associated with presynaptic neurons that have different frequency tuning. For example, duration-tuned neurons in various species of animals for processing temporal information belong to the first category, whereas delay-tuned neurons in the mustached bat for processing spectrotemporal information belong to the second category. 3. Biosonar signals and combination-sensitive neurons The bio-sonar pulse of a mustached bat is composed of four harmonics (H1e4) consisting of a constant frequency (CF) and frequency modulated (FM) components. Therefore, each pulse consists of eight components: CF1e4 and FM1e4 (Fig. 1A). CF1 is ~30 kHz and FM1 sweeps from 30 kHz to 24 kHz. Sixteen types of combination-sensitive neurons were found in the auditory cortex of the mustached bat by 1984. Thirteen types of neurons out of the 16 are tuned to combinations of the first harmonic and the higher harmonics (Fig. 1B). “Combination-sensitive” means that a neuron shows a facilitative response to a combination of multiple signal elements that is larger than the algebraic sum of the responses to the individual signal elements. There are two major categories of combination-sensitive neurons: those acting as coincidence detectors with (Fig. 1B, 9e15) or without (Fig. 1B, 1e5 and 16) delay lines. They are respectively specialized for processing spectrotemporal or spectral information. Types 1e3 and 9e15 in Fig. 1B are respectively called “CF/CF” and “FMeFM” neurons. CF/CF neurons are tuned to a combination of 2e3 signal elements that simultaneously occur or greatly overlap. They are broadly tuned to zero ms echo delay (Fig. 1C; Suga et al., 1983). Coincidence detectors without delay lines have been symbolized by a forward slash “/“

(Suga et al., 1978). On the other hand, FMeFM neurons are tuned to a combination of 2e4 signal elements with a specific delay between them, the best delay (Fig. 1D; O'Neill and Suga, 1979, 1982). Coincidence detectors associated with delay lines have been symbolized by a dash “e“ (Suga et al., 1978). CF/CF neurons form a map for a systematic representation of Doppler shifts (velocity information) in the CF/CF area. On the other hand, FMeFM neurons form a map for systematic representation of echo delays (distance information) in the FF area (Fig. 2B). [Tang and Suga (2008) renamed the FMeFM area as the FF area. FF stands for frequency modulationefrequency modulation.] 4. Differences in data acquisition and processing between laboratories Suga and his collaborators had determined the maximum facilitative response of a FMeFM neuron as the response to the FM1eFMn stimulus (n ¼ 2, 3 or 4) set at its best frequency sweep, best amplitude and best delay for facilitation. If the best amplitude of the pulse was not identifiable as a single value, it was set at 60e80 dB SPL to mimic vocal self-stimulation. Acoustic stimuli were delivered to an awake or anesthetized bat from a loudspeaker placed at a 73 cm distance in front of the bat, because the bat's ears would be equally stimulated during a target-directed flight (O'Neill and Suga, 1982; Suga et al., 1983; Yan and Suga, 1996a). On the other hand, Portfors and Wenstrup (1999, 2004, 1999), Hagemann et al. (2011) and Macias et al. (2012) had determined the maximum facilitative response of a FMeFM neuron as the response to the FM1eFMn stimulus set at its best frequency sweep, 10 dB above minimum threshold and best delay for facilitation. Macias et al. (2012) defined a delay-tuning curve or area with a criterion of 50% of the maximum facilitative response of a neuron, instead of just-noticeable facilitation. In the research by Wenstrup and his coworkers, Hagemann et al. and Macias et al., acoustic stimuli were delivered to an awake bat from a loudspeaker placed at a 10 cm distance from the bat's ear, 25 contralateral to the inferior colliculus or auditory cortex to be studied. Other differences in data acquisition and processing between different laboratories will be described later, as necessary. 5. Delay-tuned FMeFM neurons and synaptic mechanisms FMeFM neurons have been found in the inferior colliculus in the midbrain, the medial geniculate body in the thalamus and the auditory cortex (Fig. 2A). They show a facilitative response to a combination of simulated pulse and echo (hereafter, pulse-echo pair) with a specific echo delay. The essential signal elements in the pulse-echo pair are pulse FM1 and echo FMn (O'Neill and Suga, 1979, 1982; Suga et al., 1983). When FMeFM neurons respond, the response latency is long to FM1, but short to FMn. When the FMn is delivered after FM1 with a delay equal to this latency difference, the neural responses to FM1 and FMn coincide and evoke a facilitative response (Fig. 3A; Suga, 1990). The basic response properties of FMeFM neurons are theoretically created by four components: “constant-latency-phasic” onneurons, delay lines, coincidence detectors and amplification (Suga, 1990; Suga et al., 1990b). A FM sound sequentially stimulates an array of peripheral auditory neurons tuned to different frequencies by sweeping across their frequency-tuning curves. Constant-latency-phasic on-neurons are ideal for coding that moment of the stimulus by discharging just one action potential with a constant latency regardless of stimulus levels (Suga, 1970; Bodenhamer and Pollak, 1981). If a neuron responds to a stimulus with multiple discharges and is spontaneously active, it is not suited for ranging. Constant-latency phasic on-neurons have been

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Fig. 1. Schematized spectrogram of the biosonar signal of the mustached bat, Pteronotus parnellii, and combinations of signal elements to which cortical combination-sensitive neurons are tuned. (A) The solid and dashed lines, respectively, show the spectrograms of the bio-sonar pulse (P) and its echo (E) that is Doppler shifted (DS) and delayed from P. The four harmonics (H1e4) of a P each consist of a long constant-frequency (CF) and a short frequency-modulated (FM) component, so that there are eight components: CF1e4 and FM1e4. Most of the sound-energy is in the second harmonic (H2), containing CF2 at about 61 kHz and FM2 sweeping from 61 kHz to about 49 kHz. (B) The combinations of signal elements in a PeE pair, to which 16 types of combination-sensitive neurons selectively respond. (C) The facilitative responses of a CF1/CF3 neuron to a PeE pair (C3) and a pair of essential signal elements: pulse CF1 and echo CF3 (C4). The neuron showed a strong phase-locked response to the echo being frequency modulated at a rate of 100/s, mimicking the echo from a flying insect, only when it was paired with the pulse (C5). (D) The facilitative response of a FM1eFM2 neuron to a PeE pair (D3) and a pair of essential signal elements: pulse FM1 and echo FM2 (D4). The neuron is tuned to a 9.3-ms delay of the echo FM2 from the pulse FM1. A FMeFM neuron showed no facilitative responses when one of the paired FM sounds swept upward (unnatural sweep direction) in frequency (D5 and D6). EFM, echo FM; EH, echo harmonic; PFM, pulse FM; PH, pulse harmonic; SFM, sinusoidal frequency modulation. Based on Suga et al. (1978, 1983), Suga (1984) and Suga et al. (1997).

found in the subcollicular auditory nuclei, such as the ventral nucleus of the lateral lemniscus (Covey and Casseday, 1991; Haplea et al., 1994; O'Neill et al., 1992). The linear correlation between FM1 response latencies and best delays was first demonstrated in the medial geniculate body in the thalamus. The longer the best delay, the longer the FM1 response latency is (the correlation coefficient, r, is 0.88). However, FMn response latencies are short and constant, regardless of the lengths of best delays. Therefore, the delay lines utilized by the FMeFM neurons are produced by FM1 responding neurons. The correlation coefficient between the differences in latency between the FM1 and FMn responses and the best delays is 0.96. Therefore, the FMn response latencies also contribute a little to determining the best delays (Olsen and Suga, 1991b). The best delays of collicular FMeFM neurons are also linearly related to the response latencies to FM1 (Yan and Suga, 1996a; Portfors and Wenstrup, 1999). A coincidence detector has two inputs: one from a FM1 responder with or through delay lines (Fig. 3, A1 and C1), and the other from a FMn responder without delay lines (Fig. 3, A2 and C2). An echo FMn is acoustically delayed from the pulse FM1 emitted by

the bat, and the amount of echo delay is linearly related to a target distance. At the coincidence detector where the neural delay of a FM1 response is equal to a FMn echo delay, the excitatory response to the echo FMn arrives at the same time as the neurally-delayed excitatory response to the pulse FM1. Then, the coincidence detector (FMeFM neuron) shows a facilitative response (Fig. 3, A3 and C3). The strength of facilitative response depends on the extent of coincidence. Thus, the FMeFM neurons are tuned to a specific echo delay: the best delay (Suga, 1990). Iontophoretic applications of a glycine or GABA-A receptor antagonist to FM1 responding neurons in the anterolateral division of the inferior colliculus shortened the best delays of FMeFM neurons in the FF area of the auditory cortex: the longer the best delay, the greater the shortening. Those drug effects indicate that inhibitory delay lines exist in the inferior colliculus (Saitoh and Suga 1995). However, the amount of shortening was less than that expected by the model proposed by Suga (1990). This small drug effect might be due to its diffusion from the injection sites to the collicular FMeFM neurons. Nataraj and Wenstrup (2005) and Sanchez et al. (2008) found that a glycine receptor antagonist eliminates the delay tuning of almost all collicular FMeFM neurons.

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Fig. 2. The auditory pathway, cortical auditory areas and delay axis in the cortex. (A) Dorsolateral view of the left cerebral hemisphere of the mustached bat (Pteronotus parnellii rubiginosus) and the branches of the median cerebral artery. The arrows indicate the ascending and descending auditory pathways. (B) The frequency (tonotopic) representation of the primary auditory cortex (AIa, DSCF and AIp) and the physiologically explored functional organization of the other areas are indicated by lines and arrows. The DSCF area has the radial frequency axis representing 60.6e62.3 kHz and the circular amplitude axis representing 13e98 dB SPL. The FF (previously, FMeFM) area consists of three major types of FMeFM neurons (FM1eFM2, FM1eFM3 and FM1eFM4), which form separate clusters. Each cluster has an axis representing target ranges from 7 to 310 cm (echo delay: 0.4e18 ms). The DF and VF areas also consist of the three clusters of FMeFM neurons and have an axis representing target ranges up to 140 or 80 cm, respectively. The CF/CF area consists of two major types of CF/CF neurons (CF1/CF2 and CF1/CF3), which are also found in separate clusters. Each cluster has two frequency axes and represents a target velocity from 2 to þ9 m/ s. The DIF area also contains two types of CF/CF neurons. The DM area has an axis representing the azimuthal location of a sound source on the contralateral side in front of the animal. This azimuthal representation is incorporated with frequency representation. The functional organization of the DP, VA, VM and VP areas remains to be further studied. The 1.0 mm scale at the bottom is for P. p. r. (rubiginosus) from Panama and P. p. p. (parnellii) from Jamaica (Suga, 1984). (C) Delay (range) axis in the FF, DF and VF areas (Suga and O'Neill, 1979; Suga and Horikawa, 1986: Edamatsu et al., 1989). AC, auditory cortex; AIa and AIp, anterior and posterior divisions of the primary auditory cortex, respectively; CBL, cerebellum; CER, cerebrum; CF, constant frequency; CN, cochlear nucleus; DF, dorsal fringe; DSCF, Doppler-shifted constant frequency; FF, frequency modulationefrequency modulation; FM, frequency modulation; IC, inferior colliculus; MGB, medial geniculate body; NLL, nucleus of the lateral lemniscus; SOC, superior olivary nucleus; VF, ventral fringe. Different laboratories have been studying different subspecies of the mustached bats: P. p. rubiginosus from Panama and Trinidad and P. p. parnellii from Jamaica and Cuba. P. p. rubiginosus from Panama is much larger in body and brain size than P. p. parnellii from Jamaica. (See the scales at the bottom of B.)

Their findings indicate that FMeFM neurons are created in the inferior colliculus and that a mechanism for creating delay lines is inhibition followed by rebound excitation (Fig. 3, A1 and C1). However, the facilitative responses of collicular FMeFM neurons with a best delay less than 4 ms do not depend on FM1-evoked inhibition (Nataraj and Wenstrup, 2005; Wenstrup and Portfors, 2011). The delay lines for these neurons may be conduction and synaptic delays (Suga, 1990; Suga et al., 1990b). FM1-evoked hyperpolarization is observed in about a half of collicular neurons studied. The remaining neurons, however, do not show it, in spite of inhibition of the response to FMn by FM1. In those neurons, the inhibition may originate from the subcollicular auditory nuclei. In collicular FM-FM neurons, the facilitation of synaptic potentials is rarely observed, so that synaptic inputs for facilitation appear to be at dendrites remote from a soma (Peterson et al., 2008). On the basis of collicular and subcollicular studies, Wenstrup et al. (2012) proposed a model shown in Fig. 3C and D. Two important aspects in the model, which were not proposed by Suga et al. (1990b), are: (1) FMn evokes a brief-glycine inhibition followed by a rebound depolarization (Fig. 3, C2) and (2) glutamate receptors such as NMDA receptors are not involved in the collicular

facilitation. Collicular FMeFM neurons have glycinergic inputs from FM1 responding neurons in the VNLL and INLL and also from FMn responding ones in the VNLL, INLL and MSO, as indicated in Fig. 3D. Since the intra-cellularly recorded responses of collicular FMeFM neurons to FM1, FMn and FM1eFMn showed neither hyperpolarization nor rebound depolarization (Peterson et al., 2008, 2009), Peterson et al. hypothesized that the coincidence of FM1-evoked rebound depolarization and FMn-evoked rebound depolarization occur at a dendrite remote from the soma of the collicular FMeFM neuron and that a facilitative response occurs at a proximal portion of that dendrite (“x” in Fig. 3D). In the medial geniculate body (Olsen and Suga, 1991b, Fig. 4A) and the auditory cortex (Suga et al., 1983; Edamatsu and Suga, 1993), the FM1 and FMn responses both are usually inhibited if FMn delay is shorter than its best delay (Fig. 4A), and it is likely that glutamate receptors play a role in facilitation. Therefore, a model proposed by Suga et al. (1990b) is different in two aspects from that proposed by Wenstrup et al. (2012). (1) The excitation evoked by FMn is followed by inhibition (Fig. 3, A2). (2) In the medial geniculate body, coincidence detection and facilitation can be evoked by glutamate via non-NMDA and NMDA receptors (Fig. 3B). It remains to be further explored whether and how FMeFM facilitation is

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Fig. 3. Neural mechanisms for creating delay-tuned neurons (hypothesis). (A and B) Suga et al.'s model (1990b) based on cortical and thalamic data. (C and D) Wenstrup et al.'s model (2012) based on collicular data. In (A) and (C), 1, 2 and 3 show the responses to FM1, FMn and FM1eFMn, respectively. FM1 and FMn stimuli are symbolized with the filled and unfilled circles, respectively. The shaded and un-shaded portions of the responses represent hyperpolarization and depolarization, respectively. Note that the response to FMn is different between the 1990 and 2012 models. FMn paired with FM1 with a delay (best delay of a neuron: BD) equal to the difference in latency (LD) between the depolarizing responses to the individual stimuli evokes a facilitative response, as shown in A3 and C3. (B) The arrays of post-stimulus-time (PST) cumulative histograms displaying the responses of a thalamic FMeFM neuron, obtained by J. A. Butman. The neuron was tuned to 1.5 ms echo delay (B1). A NMDA receptor antagonist (APV) abolishes only the burst of spikes, slow component, of the delay-dependent facilitative response of the neuron to FM1eFMn pairs (B2). These three series of PST cumulative histograms were obtained 3 min prior to (control), immediately after (APV), and 10 min after (recovery) an iontophoretic application of 100 nA APV to the FMeFM neuron. E, echo FMn stimulus alone; N, no stimulus; P, pulse FM1 stimulus alone. The horizontal bar at the bottom indicates the PeE, i.e., FM1eFMn paired stimuli with different echo delays ranging from 0.0 to 4.5 ms. Each PST cumulative histogram is 150 ms long. The neuron showed the best response to a 1.5 ms echo delay (Suga et al., 1990b). In (D), a dendrite of a collicular FMeFM neuron has glycinergic (Gly) inputs from FM1 and FMn responders. The superimposition of rebound depolarization evoked by these inhibitory inputs causes a facilitative response (inset and C3) at the proximal portion of the dendrite, indicated by “x”. Needless to describe in terms of the model, the collicular FMeFM neuron has many other inputs unrelated to the FMeFM facilitation. GABA, gamma-aminobutyric acid; Glu, glutamate, INLL, intermediate nucleus of the lateral lemniscus; MSO, medial superior olive, VNLL, ventral nucleus of the lateral lemniscus (Based on Wenstrup et al., 2012).

shaped not only in the inferior colliculus, but also in the medial geniculate body and the auditory cortex.

6. Comparison between collicular and thalamic FMeFM neurons Mittmann and Wenstrup (1995) and Yan and Suga (1996a) found three types of FMeFM neurons (FM1eFM2, FM1eFM3 and FM1eFM4) in the central nucleus of the inferior colliculus. As described above, their basic response properties are created in the inferior colliculus, because a glycine receptor antagonist eliminates delay-tuned facilitation in almost all collicular neurons studied and a GABA-A receptor antagonist does so in about one-third of them (Nataraj and Wenstrup, 2005). In the thalamus, the three types of FMeFM neurons are clustered in the dorsal division (Olsen and Suga, 1991b), more specifically, in the rostral pole nucleus of the dorsal division (Wenstrup et al., 1994; Wenstrup, 1999). The response properties of thalamic FMeFM neurons are different from those of collicular ones in several aspects, as reviewed below.

6.1. Threshold and best amplitude for facilitation A change in threshold due to facilitative responses to FM1eFMn stimuli is small and insignificant in the inferior colliculus (Portfors and Wenstrup, 1999). However, it is large in the thalamus. According to Olsen and Suga (1991b), almost a half of thalamic FMeFM neurons do not respond to FM1 and/or FMn at any amplitude tested, but respond to FM1eFMn pairs. The thresholds for their facilitative responses to FMn are as low as 17 dB SPL (Fig. 4C). Compared with collicular FMeFM neurons, thalamic ones are more specifically responsive to combination of two sounds than individuals. Some collicular FMeFM neurons are amplitude-tuned as well as delay-tuned for facilitation (Yan and Suga, 1996a). About one-fifth of collicular FMeFM neurons show upper-thresholds for facilitation (Macias et al., 2012). Thalamic FMeFM neurons are also tuned to specific amplitudes as well as specific delays. Their best amplitudes for facilitation are 50e70 dB SPL for FM1 and 10e80 dB SPL for FMn (Fig. 4D and E). Most of thalamic FMeFM neurons do not show facilitative responses to an intense FMn. They show upperthresholds for facilitation (Olsen and Suga, 1991b), and thus differ from collicular FMeFM neurons.

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Fig. 4. Delay-dependent facilitation and inhibition, decrease in threshold by facilitation, and best amplitudes for facilitation of thalamic FMeFM neurons. (A) Inhibition and facilitation of the response of a FM1eFM4 neuron to FM4 as a function of FM4 delay from FM1. The array of PST cumulative histograms displays the responses to FM1 alone, FM4 alone and FM1eFM4 pairs with different FM4 delays ranging from 0.0 to 13 ms. These FM stimuli were fixed at the best FM and best amplitude for facilitation. (B and C) Decrease in minimum threshold, i.e., increase in sensitivity, due to facilitation is shown by plotting the threshold for FM1 (B) or FMn (C) alone against that for FM1eFMn pair. In a FM1eFMn pair, FM1 or FMn was fixed at the best amplitude and best delay for facilitation of a given neuron and the other was varied for the measurement of threshold for facilitation. Almost all data points are above the unity slope line. The points within the top brackets marked NR indicate no responses to FM1 or FMn presented alone at amplitudes from 0 to 107 dB SPL, but facilitative responses with low thresholds. (D and E) Distributions of FM1 (D) or FMn (E) best amplitudes for facilitation of FMeFM neurons show the data obtained from FM1eFM2 (black bars), FM1eFM3 (hatched bars) and FM1eFM4 (white bars) neurons (Olsen and Suga, 1991b).

In some FMeFM neurons, thresholds for facilitative responses become slightly lower for longer echo delays, so that their delay-tuning curves are tilted. The tilting of cortical delay-tuning curves with echo delays increases with an increase in best delay (Hagemann et al., 2011). However, the tilting of collicular ones shows no such correlation. Collicular FMeFM neurons are level tolerant in processing distance information, compared with cortical ones (Macias et al., 2012). 6.2. Strength of facilitation Strength of facilitation has been expressed by a facilitation index (FI) that is defined as (Rc  Rp  Re)/(Rc þ Rp þ Re). Rc, Rp and Re are respectively the responses (numbers of action potentials) of a neuron to a pulse-echo (FM1eFMn) pair, pulse (FM1) alone and echo (FMn) alone “at their best amplitudes for facilitation” according to Yan and Suga (1996a), Suga and Horikawa (1986) and Olsen and Suga (1991b), but “at 10 dB above minimum threshold for facilitation” according to Portfors and Wenstrup (1999, 2004, 1999). Suga and his collaborators calculated the strength of facilitation with the maximum responses of FMeFM neurons at their best delays and best amplitudes,

because almost all of them were tuned to the combination of a specific delay and specific amplitude of FMn (Fig. 4E). Yan and Suga (1996a) found that the FI “based on best amplitude” is larger for thalamic FMeFM neurons than collicular ones, and concluded that thalamic neurons are more specialized for processing distance information than collicular ones in terms of magnitude of facilitation and sharpness of delay tuning, which is described next. Portfors and Wenstrup (1999), however, found that the FI “based on 10 dB above minimum threshold” is not different between thalamic and collicular neurons and concluded that “the basic response properties of FMeFM neurons do not undergo extensive transformations with ascending auditory processing”. The FI distribution in their paper is bimodal and that the percentage of neurons with large FIs is much larger in the thalamus than in the inferior colliculus. Their conclusion is based on the measurement at 10 dB above minimum threshold for facilitation, not on the measurement at best amplitude for facilitation. The comparisons between the data obtained at two different stimulus levels are difficult, because facilitative responses are non-linear and because delay-tuning curves are not simple triangular shape.

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6.3. Sharpness of delay tuning curves and best delays The sharpness of a delay-tuning curve has been expressed by a “Q-50%” or “50% delay-width”. The Q-50% is defined as a best delay divided by 50% delay-width “at the best amplitude for facilitation” in the paper of Yan and Suga (1996a), but “at 10 dB above minimum threshold for facilitation” in the paper of Portfors and Wenstrup (1999). The 50% delay-width is the width of a delay-tuning curve at 50% of a maximum response evoked by FMn “at its best amplitude for facilitation” in the papers of Yan and Suga (1996a), Suga and Horikawa (1986), Olsen and Suga (1991b) and Misawa and Suga (2001). Because FMeFM neurons are tuned to a specific echo amplitude (best amplitude) as well as a specific echo delay (Fig. 5A), the 50% delay-widths were measured “at the best amplitude” for FMeFM facilitation by Suga and his collaborators. On the other hand, the 50% delay-widths are the width of a delay-tuning curve “at 10 dB above minimum threshold for facilitation” in the papers of Portfors and Wenstrup (1999, 2004) and Hagemann et al. (2011). Q-50%s computed “at the best amplitude for facilitation” are larger in the thalamus than in the colliculus. They are not correlated to best delays in the inferior colliculus, but weakly correlated in the thalamus (Fig. 6E; Yan and Suga, 1996a). In the thalamus, the 50% delay-widths are correlated to their best delays: the longer the best delay, the wider the delay tuning is (Fig. 6B and D; Olsen and Suga, 1991b). In thalamic FMeFM neurons with best delays longer than 4 ms, FM1 stimulus evokes inhibition that begins at the onset of the stimulus and ends before FM1-evoked excitation. The duration of this inhibition is positively correlated with best delay (Olsen and Suga, 1991b). If the duration of a rebound excitation is longer for longer-lasting inhibition evoked by FM1, the delay-width of a delaytuning curve will be wider for a longer best delay. On the contrary, the 50% delay-widths measured “at 10 dB above minimum threshold” are not correlated at all to best delays in the inferior colliculus (Portfors and Wenstrup,1999), but are correlated in the thalamus (Wenstrup, 1999), although the correlation is poor compared with that based on the best amplitudes (Olsen and Suga, 1991b). Such a difference between the colliculus and thalamus suggests an improvement in organization of FMeFM neurons for echodelay processing. However, Macias et al. (2012) found that the delay-widths of collicular neurons measured at 10 dB above minimum threshold are correlated with best delays, as in the auditory cortex (Hagemann et al., 2011). The correlation coefficient in the inferior colliculus is quite different between the data obtained by Portfors and Wenstrup (1999) and Macias et al. (2012): 0.3 vs. 0.6. This difference may be due to a difference in data acquisition between them. Portfors and Wenstrup (1999, 2004) wrote that unlike the data obtained by Yan and Suga (1996a) and Olsen and Suga (1991b), 50% delay-widths of delay-tuning curves are not related with best delays, and the sharpness, Q-50%, of delay tuning is similar between the collicular and thalamic FMeFM neurons. It should be noted that the delay-widths of single neurons measured at their best amplitudes are broader than those measured at 10 dB above minimum threshold with few exceptions, and that the differences described above might be due to the data obtained at two different stimulus levels. In the midbrain of the big brown bat which emits FM pulses for echolocation, Q-50%s of delay tuning curves measured “at best amplitudes for facilitation” are correlated with best delays: the longer the best delays, the wider the delay tuning curves (Dear and Suga, 1995). 6.4. Delay axis The dorsal division of the medial geniculate body has a delay axis, representing 0e23 ms (Olsen and Suga, 1991b) or 1e24 ms

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(Wenstrup, 1999). The best delays of collicular FMeFM neurons sampled are 0.5e17.5 ms (Yan and Suga, 1996a) or 0e20 ms (Portfors and Wenstrup, 2001). The delay axis of the FF area in the auditory cortex represents 0.4e24 ms (Fig. 2C; Suga and O'Neill, 1979). The population of FMeFM neurons with best delays longer than 18 ms is very small. At any rate, there is no sign that the delay axis becomes longer at the higher levels. All ascending nerve fibers enter the inferior colliculus from its ventral end and spread more-or-less ventrodorsally. Suga (1990) hypothesized that short delay lines (<4 ms) are created by conduction and synaptic delays, whereas long delay lines (>4 ms) are created by inhibition that evokes rebound excitation or by both conduction/synaptic delays and inhibition. Yan and Suga (1996a) noticed that best delays progress from short to long along the ventrodorsal axis of the inferior colliculus. Such a distribution of best delays might be related to the ascending nerve fibers spreading in the inferior colliculus, in which the latencies of responses to single tones change from 4 to 12 ms along the ventrodorsal axis (Hattori and Suga, 1997). However, this view was not supported by Portfors and Wenstrup (2001). They found that the FMeFM neurons with different best delays are randomly located in the medial division of the inferior colliculus. However, the colliculus probably holds a delay axis. The following provides multiple reasons for further studies on the collicular delay axis: (1) As Yan and Suga (1996a) found, six electrode penetrations in Portfors and Wenstrup's paper (2001, Figs. 3AeC and 4AeC) show a clear increase in best delay along the ventro-dorsal axis of the inferior colliculus. This fact suggests that part of a cluster of collicular FMeFM neurons has a ventro-dorsally oriented delay axis. In other electrode penetrations, however, best delays do not increase. This might be due to convoluted or twisted iso-best delay contours. Therefore, one needs to carefully reconstruct the recording in 3D. (2) The FF area of the auditory cortex has a delay axis and frequency-versus-frequency coordinates, as studied with FM1eFMn pairs. The best delays of FMeFM neurons change together with the initial-frequencies of FM1 and FMn for best facilitation (Misawa and Suga, 2001). Collicular FMeFM neurons are tuned in both delay and frequency (Portfors and Wenstrup, 2001). Therefore, it is possible that best delays are not random but related to the collicular frequency map. (3) Collicular FMeFM neurons are systematically modulated by cortical FMeFM neurons in the FF area, according to the specific relationship in best delay between stimulated cortical and recorded collicular FMeFM neurons (Yan and Suga, 1996b). Because the FF area has a delay axis, this systematic modulation suggests that FMeFM neurons with different best delays are not randomly arranged in the inferior colliculus. (4) In the big brown bat, collicular duration-tuned neurons are tuned in both duration and frequency. Their best durations are positively correlated with their best frequencies for the collicular tonotopic map (Jen and Wu, 2006). The neural mechanism underlying duration tuning is coincidence detection associated with rebound response following inhibition (Covey and Casseday, 1999), as in the case of delay tuning. And glycinergic and GABAergic inhibition plays an essential role in creating both the delay- and duration-tuned neurons (Nataraj and Wenstrup, 2005; Casseday et al., 1994, 2000; Fuzessery and Hall, 1999; Jen and Feng, 1999; Jen and Wu, 2005). Therefore, it may be speculated that the inferior colliculus of the mustached bat also has an axis or a gradient for delay representation.

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Fig. 5. Tuning of a FMeFM neuron to a specific echo delay and specific echo amplitude and a facilitative response of a FMeFM neuron to a temporal-pattern-simulating (TPS) stimulus. (A) Iso-spike-count contours indicating tuning of a cortical FM1eFM2 neuron to a 3.5-ms echo delay and 62 dB SPL echo amplitude. Each dot indicates an echo delay and amplitude where a number of spikes per paired stimulus was obtained by presenting the array of pulse-echo pairs in a TPS stimulus delivered 50 times. The contour lines were drawn on the bases of these data points. Each number indicates a number of spikes per 50-paired stimuli. The dashed line is the delay-tuning curve audio-visually measured with standard stimuli: PeE pairs delivered at a rate of 4 pairs/s. FM1, 30.45e24.45 kHz swept at 62 dB SPL best amplitude; FM2, 62.54e50.54 kHz at varied dB SPL. (B) A TPS stimulus consists of 22 pairs of a pulse and an echo. In the TPS stimulus, a repetition rate of a pair increases and an echo delay shortens as in a target-directed flight. “1” shows only the timing pulses of a TPS stimulus. Neither TPS pulse alone (2) nor TPS echo alone (3) excites a cortical FMeFM neuron with a 2.4 ms best delay, but a TPS pulse-echo pair does (4). The data were obtained from the FF area of un-anesthetized (UA) mustached bats (Suga and Horikawa, 1986).

(5) In the big brown bat, the tonotopic axis of the inferior colliculus is straight, running from dorsal to ventral (Casseday and Covey, 1989). However, it is twisted in the mustached bat, starting from the antero-lateral portion of the inferior colliculus representing low frequencies, goes to its dorsoposterior potion, and ends at its antero-medial portion representing high frequencies (Zook et al., 1985; Hattori and

Suga, 1997). This twisted tonotopic axis might result in incomplete 2D reconstructions. (6) For mapping experiments, it is essential to obtain many data points from several electrode penetrations, recording at least three data points per penetration, across a single inferior colliculus within one or two days. Pooling data obtained from many nuclei might mislead us because of variations in

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Fig. 6. Delay-tuning curves and sharpness of delay tuning (50% delay-widths and Q-50%) of cortical (FF area), thalamic (MGBd) and collicular (ICc) FMeFM neurons. (A) Delaytuning curves of seven FMeFM neurons in the FF area. Since they did not show facilitative responses to strong echoes, their tuning curves were closed at top (O'Neill and Suga, 1982). (B) Echo delay-response (spike count) curves of six thalamic FMeFM neurons. For each neuron, FM1 and FMn were presented at their best amplitudes. The response magnitude is expressed as a percentage of the maximum response at the best amplitude and best delay for facilitation (Olsen and Suga, 1991b). (C and D) The relation between best delays and 50% delay-widths of cortical (C, Suga and Horikawa, 1986) and thalamic (D, Olsen and Suga, 1991b) FMeFM neurons. The delay-width was measured at the 50% response level, referring to the maximum response at the best amplitude for facilitation. (E) The relation between best delays and Q-50%s of thalamic (B) and collicular () FMeFM neurons. Q-50% is best delay divided by 50% delay-width at best amplitude. MGBd, dorsal division of the medial geniculate body; ICc, central nucleus of the inferior colliculus (Yan and Suga, 1996a).

electrode placements and individual maps (Evans et al., 1965; Merzenich et al., 1975). 7. Cortical FMeFM neurons Since FMeFM neurons were first found in the FF (previously, FMeFM) area of the auditory cortex (Suga et al., 1978), their response properties had been most extensively studied. Therefore, I will first review those in relation to the response properties of subcortical FMeFM neurons. 7.1. Thresholds, best amplitudes and delay-widths for facilitation All collicular FMeFM neurons respond well to single tone bursts (Macias et al., 2012), but only a half of cortical ones do (Hagemann et al., 2011). According to qualitative observations, cortical FMeFM neurons tend to respond less to individual FM sounds, but more to

combinations of FM sounds, compared with their subcortical counterparts (Taniguchi et al., 1986; Olsen and Suga, 1991b). Onethird of cortical FMeFM neurons do not respond at all to FMn at any amplitude tested, but respond to FM1eFMn pairs. The threshold drops as much as 90 dB by facilitation of sub-threshold response (Suga et al., 1983). It is clear that cortical FMeFM neurons are quite different from collicular ones in response properties. The facilitative responses of cortical FMeFM neurons are none or poor to an intense FMn, so that they show lower and upperthresholds, like those of thalamic FMeFM neurons. Their isospike count contour lines and delay-tuning curves are mostly spindle shaped or round (Fig. 6A; O'Neill and Suga, 1982; Suga and Horikawa, 1986). The magnitude of facilitative responses usually becomes maximal at a specific amplitude: the best amplitude. FMn best amplitudes for facilitation tend to be slightly lower and more widely distributed than FM1 best amplitudes for facilitation (Suga et al., 1983). The amplitude tuning of FMeFM neurons is sharper

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in the cortex than in the colliculus, because closed delay tuning curves as shown in Fig. 6A are much more common in the auditory cortex than in the inferior colliculus. Cortical FMeFM neurons are tuned to a specific combination of echo delay and echo amplitude (O'Neill and Suga, 1982; Suga et al., 1983). As in the thalamus, 50% delay-widths of cortical delay tuning curves measured at best amplitudes for facilitation are linearly related to best delays (Fig. 6C; Suga and Horikawa, 1986). Because FMeFM neurons are tuned to a specific echo delay and echo amplitude, they would respond best to a target of a specific cross-sectional area at a specific distance, i.e., to a specific target size. FM1eFM4 neurons are theoretically better suited for fine characterization of small targets than FM1eFM2 neurons, because FM4 has a much shorter wavelength and wider bandwidth than FM2 has. The delay-tuning curves are broad for neurons tuned to long best delays, and the curves tuned to different echo delays greatly overlap with each other (Fig. 6A). The array of FMeFM neurons with different best delays would process the scene within three meters, including a primary target and objects in front and behind it. FMeFM neurons tuned to short echo delays respond well to each pulse-echo pair delivered at a rate of 100 pairs/s, the rate of pulse emission in the terminal phase of echolocation (O'Neill and Suga, 1979, 1982). Delay-tuning curves of cortical FMeFM neurons with long best delays are often tilted so that they would respond best to the echoes from approaching targets over decreasing distances, as echo delay shortens and echo amplitude increases (O'Neill and Suga, 1982; Hagemann et al., 2011). The tilt of cortical delay-tuning curves with echo levels increases with an increase in best delay (Hagemann et al., 2011). The best delays of collicular FMeFM neurons, however, usually do not change with echo levels. Their responses are level-tolerant, compared with cortical ones (Macias et al., 2012).

increments (~2.0 cm increments in distance) for best delays up to eight ms, but in the increments larger than that for best delays longer than eight ms (Fig. 2C; Suga and O'Neill, 1979). Iso-best delay lines cross the three subdivisions of the FF area without interruption. “Multi-combination-sensitive” neurons exist in a ~100 mm wide band along the boundary between the subdivisions. For example, FM1eFM2,4 neurons are at the boundary between the FM1eFM2 and FM1eFM4 subdivisions. In rare cases, FM1eFM2,3,4 neurons are found where the boundaries of the three subdivisions touch each other. The multi-combination-sensitive neurons respond best when more than two signal elements are combined (Fig. 7). Their best amplitudes for facilitation are slightly lower for multicombination stimuli than for single combination stimuli (Misawa and Suga, 2001). Multi-combination-sensitive neurons are rarely found in the thalamus (Olsen and Suga, 1991b). The great majority of multi-combination-sensitive neurons are probably produced within the FF area by convergence of delay-tuned FMeFM neurons with an identical best delay, but with different FMeFM combination-sensitivities. In addition to delay-tuned FMeFM neurons, there are “tracking” FMeFM neurons in the FF area. Tracking FMeFM neurons shorten their best delays as pulse-echo stimuli change as in the pulse-echo pairs during a target-directed flight (O'Neill and Suga, 1979, 1982). Tracking FMeFM neurons have not yet been reported in the inferior colliculus. They may be produced in the thalamus and/or cortex by convergence of delay-tuned FMeFM neurons with different best delays, but with an identical FMeFM combination-sensitivity. Tracking FMeFM neurons are much smaller in number than delay-tuned FMeFM neurons. They form independent functional columns in the three divisions of the FF area (O'Neill and Suga, 1982). In this article, FMeFM neurons always mean delay-tuned FMeFM neurons.

7.2. Inhibition and inhibitory delay-tuning curves

7.4. Frequency-versus-frequency coordinates

As found in the thalamus (Fig. 4A), the responses of cortical FMeFM neurons to FM1 alone and FMn alone are inhibited by FM1eFMn stimuli when FMn delay from FM1 is shorter than their best delays. Therefore, it is interpreted that FM1 response consists of inhibition followed by rebound excitation, and that FMn response consists of excitation followed by inhibition. In addition, the response to FMn alone is inhibited when FMn is delayed from FM1 more than their best delays. Inhibitory delay-tuning curves measured with FM1 and FMn appear not only prior to an excitatory delay-tuning curve but also afterward (Edamatsu and Suga, 1993). In collicular FMeFM neurons, such inhibitory delay-tuning curves are apparently exist (Nataraj and Wenstrup, 2005), but have not yet been measured and are not incorporated into the model shown in Fig. 3C and D.

The FF area does not reveal tonotopic organization when studied with tone bursts, because single tone stimuli do not or poorly excite most neurons in this area (Suga et al., 1978). However, it reveals frequency-versus-frequency coordinates when studied with FM1eFMn pairs. Namely, the initial frequency of FM1 for best facilitation changes along the rostrocaudal axis of the FF area and that of FMn for best facilitation changes along the dorsoventral axis (Misawa and Suga, 2001). The FF area is specialized for the systematic representation of echo delays, as already described. The frequency-versus-frequency coordinates indicate that FMeFM neurons are produced within the most basic framework of the auditory system, the tonotopic map.

7.3. Delay axis, multi-combination-sensitive neurons and tracking neurons

The three types of FMeFM neurons (FM1eFM2, FM1eFM3 and FM1eFM4) are clustered in the dorsal (DF) and ventral (VF) fringe areas of the auditory cortex, in addition to the FF area (Fig. 2B; Suga and Horikawa, 1986; Edamatsu et al., 1989; Fitzpatrick et al., 1998b). The FF and DF areas respectively receive inputs from the lateral and medial parts of the rostral pole of the medial division of the medial geniculate body (Pearson et al., 2007). The FF, DF and VF areas mutually project (Fitzpatrick et al., 1998a) and modulate the delaydependent responses and delay tuning of FMeFM neurons, as described later. The DF area is smaller than the FF area and consists of three clusters of FMeFM neurons, as in the FF area. Each cluster has an echo delay axis up to 9 ms (Suga and Horikawa, 1986). The VF area is much smaller than the DF area and has an echo delay axis up to 5 ms (Edamatsu et al., 1989). The delay axis is different in length,

The three types of FMeFM neurons, FM1eFM2, FM1eFM3 and FM1eFM4, are separately clustered in the FF area, forming three elongated subdivisions (Fig. 2B). In each subdivision, neurons arranged orthogonally to the cortical surface have identical best delays. That is, the FF area shows the columnar organization in terms of best delays and FMeFM combinations. On the other hand, the best delays of neurons arranged along the rostro-caudal axis of the FF area systematically change from 0.4 to 18 ms, indicating that each subdivision has a target range axis from 7 to 310 cm. Since the average inter-neuronal distance in the cortical plane is ~20 mm, adjacent neurons would express echo delays in ~0.12 ms

7.5. Three cortical areas consisting of FMeFM neurons

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Fig. 7. Facilitative responses and facilitative frequency-tuning curves of FM1eFM2,3,4 neurons in the FF area. (A) Post-stimulus-time (PST) histograms displaying responses of a single FM1eFM2,3,4 neuron to different combinations of harmonics of a pulse-echo pair. Its best delay was 2.0 ms. This neuron showed poor or no responses to FM1 alone (a) or FM2e4 alone (bed), but strong facilitative responses to combinations such as FM1 þ FMn (eeg), FM1 þ FM2 þ FM3 (k), FM1 þ FM2 þ FM4 (l), FM1 þ FM3 þ FM4 (m). It responded to neither FM2 þ FM3 (h), FM2 þ FM4 (i), nor FM3 þ FM4 (j). The responses to the combinations of three signal elements (kem) were greater than those to the combinations of two signal elements (eeg). (B) Facilitative frequency-tuning curves of another FM1eFM2,3,4 neuron. These curves were measured with a pair of FM sounds in which one was varied in frequency sweep and amplitude while the other was fixed at best frequency sweep and best amplitude for facilitation. The best delay of the neuron was 6.9 ms. A best FM sound is expressed by the center frequency of its frequency sweep. The FM1 facilitative frequency-tuning curves were measured with FM1 paired with either FM2 or 3 or 4 fixed at “x”. The FM2e4 facilitative frequency-tuning curves were measured with FM2 or 3 or 4 paired with FM1 fixed at “x”. The horizontal arrow and number below each curve show the best FM sweep and its center frequency for facilitation. The data were obtained from the FF area of an un-anesthetized bat (Misawa and Suga, 2001).

but its slope (best delay/mm along the delay axis) is the same between the FF, DF and VF areas (Fig. 2C). The response properties of FMeFM neurons are somewhat different between the DF and FF areas. The 50% delay-widths of delay-tuning curves measured at best amplitudes for facilitation are linearly correlated to best delays in both the areas. But the correlation coefficient is smaller in the DF area than in the FF area. FMeFM neurons in the DF area show greater trial-to-trial fluctuations in response magnitude than those in the FF area do, indicating that they are more influenced by non-auditory inputs than neurons in the FF area (Suga and Horikawa, 1986). In target-directed flight, the rates of pulse emissions increase and echo delays shorten. Temporal-pattern-simulating (TPS) stimuli simulate these changes (Fig. 5, B1). A question was whether FMeFM neurons respond to TPS stimuli as they do to standard stimuli that are delivered at a fixed rate (4 pulse-echo pairs/s) to a bat, because cortical FM-FM neurons have inhibitory delay regions sandwiching a facilitative delay tuning curve. The facilitative responses of FMeFM neurons in the FF and DF areas to the TPS stimuli are similar to those to the standard stimuli. Their best delays measured with the TPS stimuli are also similar to those measured with the standard stimuli (Fig. 5B). There are no noticeable differences in responses to the TPS stimuli between the FF and DF areas (Suga and Horikawa, 1986). For repetitive stimuli with a FM1eFMn pair, the facilitative responses of neurons in the VF area are fast-adapting, but those in the FF area are slow-adapting. The VF area is less suited for processing the echoes in the terminal phase of a target-directed flight than the FF area, although it represents only short echo delays. The correlation between 50% delay-widths and best delays is much weaker in the VF area than in the FF area. The delay-tuning curves of VF neurons measured with “double echo” (FM1eFMneFMn) stimuli are narrower than those measured with “single echo” (FM1eFMn) stimuli. The sharpening of the curves by the second echo is larger in

the VF area than in the FF area. As in the FF area, most of the FMeFM neurons in the VF area have a facilitative delay-tuning curve sandwiched by inhibitory regions (Edamatsu and Suga, 1993). Unlike FMeFM neurons in the FF area, those in the VF area are poor in responding to pulse-echo pairs simulating those in the terminal phase of a target-directed flight in spite of their short best delays; adapt fast to repetitive stimuli; are insensitive to the direction of frequency sweep; and respond best to FMn that is not Doppler-shifted. The response properties of FMeFM neurons are clearly different between the VF and FF areas. The VF area may be involved in ranging nearby objects when the bat is hanging down from the ceiling of a cave (Edamatsu and Suga, 1993). The functional role of the VF area remains to be explored. At any rate, cortical FMeFM neurons clustered in the VF area are quite different from those in the inferior colliculus. One may consider that target distance analysis is critical at short distances, so that short echo delays are represented in the three cortical areas, i.e., by a large number of neurons. However, it is more likely that these three areas function differently from each other, because the connection with the amygdala is absent for the FF area and weak for the DF area, but strong for the VF area. The connections with other brain regions are also different for these three areas (Fitzpatrick et al., 1998a). 7.6. Cortico-cortical modulation of delay tuning Electrical stimulation of FMeFM neurons in the FF area (i.e., FF neurons) facilitates the responses of “delay-matched” FF neurons (neurons with the same best delay as those of the stimulated ones) at their best delays without shifting their best delays and delay tuning curves. However, it shifts the best delays and delay tuning curves of “delay-unmatched” FF neurons away from the best delay of the stimulated neurons. These shifts are called “centrifugal” best delay shifts (Fig. 8A). Such shifts are due to strong lateral inhibition.

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Fig. 8. Cortico-cortical modulation of FMeFM neurons in the FF and DF areas. (A and B) Facilitation of “best delay (BD)-matched” neurons and BD shifts of “BD-unmatched” neurons evoked by electrical stimulation of cortical FMeFM neurons. There are two types of BD shifts: “centrifugal” (A) and “centripetal” (B) (Suga and Ma, 2003). Electrical stimulation of neurons in the FF area evokes centrifugal BD shifts, but stimulation of neurons in the DF area evokes centripetal BD shifts (Tang and Suga, 2009). (C and D) Augmentation of the responses of a FF neuron with a 6-ms best delay (open circle) evoked by electric stimulation (arrow) of BD-matched DF neurons (C). The arrays of PST histograms display the facilitative responses of the FF neuron to paired stimuli obtained before (C1), 62 min after (C2), and 122 min after (C3) electric stimulation (ES) of DF neurons. The sound stimuli were pulse (P) alone, echo (E) alone and PeE pairs with different echo delays ranging from 0.0 to 19 ms. The three delay response curves in D are based on the arrays of histograms in C. (E and F) The centripetal BD shift of a FF neuron with a 10-ms best delay (open circle) evoked by electric stimulation (arrow) of BD-unmatched DF neurons tuned to a 4-ms delay. The stimulated and recorded neurons in CeF were FM1eFM2 neurons. The data were obtained from un-anesthetized bats (Tang and Suga, 2008).

Elimination of cortical inhibition by a GABA-A receptor antagonist applied to the stimulation site evokes the best delay shifts of delayunmatched neurons toward the best delays of the antagonistaffected neurons. These shifts are called “centripetal” best delay shifts (Fig. 8B). Therefore, cortical delay tuning depends on the balance between excitation and inhibition (Suga et al. 2000; Xiao and Suga, 2004). Electric stimulation of FF neurons also evokes the same changes as above in the contralateral FF (Tang et al., 2007), ipsilateral DF (Tang and Suga, 2008), and ipsilateral VF (Tang and Suga, 2009) areas, as well as in the ipsilateral inferior colliculus (Yan and Suga, 1996b). Cortico-cortical interactions improve and adjust delay tuning and the organization of the delay map (Suga et al., 2002; Suga, 2012). The changes evoked by electric stimulation of FMeFM neurons in the DF area (i.e., DF neurons) are different from those evoked by the stimulation of FF neurons. Namely, the delay-unmatched DF neurons show centripetal best delay shift, whereas the delaymatched DF neurons do not shift their best delays and are facilitated at their best delays, as in the FF area. Electric stimulation of DF neurons also evokes the same changes as above in the ipsilateral FF

(Fig. 8CeF; Tang and Suga, 2008) and contralateral DF (Tang and Suga, 2009) areas. Electric stimulation of FMeFM neurons in the VF area also evokes centripetal best delay shifts in the FF area (Tang and Suga, 2008). Tang and Suga (2009) found that the centripetal shifts are 2.5 times larger than the centrifugal shifts. They suggested that centrifugal shifts shape the selective neural representation of a specific target distance, whereas the centripetal shifts expand the representation of the selected target distance to enhance extraction of target information at that specific distance. Delay tuning of cortical FMeFM neurons in the three areas is improved and adjusted by cortico-cortical interactions consisting of positive feedback associated with lateral inhibition (Xiao and Suga, 2004; Tang et al., 2007; Tang and Suga, 2008, 2009). There may be no such intrinsic interactions in the inferior colliculus. 7.7. Corticofugal modulation of delay tuning The corticofugal system forms “tuning-specific” positive feedback associated with lateral inhibition (Suga et al., 2002; Suga,

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2008; Xiao and Suga, 2002, 2004; Ma and Suga, 2004). Reversible inactivation of the entire FF area in the cortex with the GABA-A receptor agonist reduces the facilitative responses of thalamic FMeFM neurons by 82% and those of collicular ones by 66%, without changing their best delays. Therefore, the facilitative responses of thalamic FMeFM neurons depend on positive feedback from the FF area more than those of collicular ones do (Yan and Suga, 1999). Reversible inactivation of the entire auditory cortex of the big brown bat decreases collicular responses to single tones by ~40% (Gao and Suga, 1998). Corticofugal feedback may amplify facilitative responses more than single tone responses. Electric stimulation of FMeFM neurons in the FF area augments the responses of best-delay-matched FMeFM neurons in the colliculus, without shifting their best delays. However, it evokes centrifugal best delay shifts and a decrease in the 50% delay-width at best amplitude of best-delay-unmatched FMeFM neurons in the colliculus. Inactivation of FMeFM neurons in the FF area evokes the changes opposite to the above (Yan and Suga, 1996b). Therefore, both the facilitative responses and delay tuning of collicular FMeFM neurons depend on the feedback loop formed by the ascending and descending auditory systems. Since corticofugal modulation of frequency tuning and facilitative responses to tone bursts is larger in the thalamus than in the colliculus (Zhang and Suga, 2000; Zhang et al., 1997), the changes in delay tuning evoked by corticofugal feedback are presumably also larger in the thalamus than in the colliculus, as the changes in facilitative responses. It has been found that plasticity in frequency tuning elicited by fear conditioning or cortical electric stimulation is short lasting in the inferior colliculus but long-lasting in the auditory cortex. The auditory cortex and corticofugal system, together with the cholinergic system, play a major role in auditory plasticity, but the inferior colliculus does not (Suga, 2012). 8. Establishing behavioral relevance of FMeFM neurons 8.1. Behavioral tests Since the response properties of FMeFM neurons had been studied with simulated pulse-echo stimuli in a soundproof room, a question was whether they respond to the pair of a self-vocalized pulse and its echo in the open air. The combination sensitivity and delay tuning of FMeFM neurons studied with simulated pulseecho pairs in the soundproof room are the same as those studied with a vocalizing mustached bat in the open air and a simulated echo triggered by the vocalized pulse. These findings indicate that their facilitative responses are indeed evoked by a combination of a vocal self-stimulation by FM1 and echo FMn stimulation. Spectral analysis of a cochlear microphonic response to a self-vocalized pulse indicates that the amount of vocal self-stimulation by its FM1 is equivalent to a sound of 70 dB SPL, when the amplitude of the vocalized pulse is 117 dB SPL at 5 cm in front of the bat's mouth (Kawasaki et al., 1988). Since all the data of FMeFM neurons had been obtained through neurophysiological studies, another question was whether the FF area is truly involved in the perception of timing information in auditory signals. In a discriminated shock-avoidance by leg flexion, reversible inactivation of the FF area temporarily impairs the bat's ability to detect a small (1.0 ms) difference in time interval between paired sounds, corresponding to echo delay, without affecting the bat's ability to detect a small (0.08%) frequency difference between the paired sounds. However, the bat's ability to detect a large (36 ms) time difference is not impaired by inactivation of the FF area. On the other hand, reversible inactivation of the cortical area specialized for the frequency representation of CF2 disrupts frequency but not delay discrimination. These findings indicate that

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the FF area is indeed involved in the perception of small time delays, such as echo delays (Riquimaroux et al., 1991, 1992). 8.2. Acuity based on FMeFM neurons Hyperacuity could emerge from an array of neurons tuned to different parameter values if their tuning curves are broad and greatly overlap with each other (Rose and Heiligenberg, 1985). Theoretical acuity based on the neurophysiological data (Suga et al., 1983; Suga, 1990) was computed as just-noticeable changes at 75% correct level in (1) the position of maximally responding neurons along the delay axis in the FF area, (2) the weighted sum of responses of all neurons in the FF area, and (3) the center of neural activity over the FF area. These just-noticeable changes depend on both the stability of neural response and absolute echo delay (target range). Assuming the response of a single neuron fluctuates 30% of the standard deviation of its mean response, the justnoticeable changes in echo delay at the range of 30e120 cm are 110e305 ms, 2.2e34 ms and 2.4e4.0 ms for (1), (2) and (3), respectively. Unlike the position of maximally excited neurons, population coding can give rise hyperacuity (Suzuki and Suga, 1991). Bats can detect 60e100 ms difference in echo delay (Simmons, 1973) and 0.5 ms echo jitter (Simmons, 1979). The just-noticeable change in the position of maximally responding neurons along the delay axis is comparable to the just-noticeable delay. 8.3. Jamming reduction The first harmonic consisting of CF1 and FM1 has less than one percent of the total energy of the emitted pulse. This weakest component in the emitted pulse is used as the reference to extract distance information. Why is distance information extracted by comparing echo FMn with pulse FM1? Let us consider that hundreds of bats are flying in a cave and that the first harmonics of their pulses are suppressed by the anti-resonance of the vocal tract. Then, in the air, there are many 2nd, 3rd and 4th harmonics produced by conspecifics, but no 1st harmonic. The combinations of these harmonics cannot excite FMeFM neurons. When a mustached bat vocalizes, the FM1 as well as FMn in the selfvocalized pulse stimulates its ears through bones and air. In this self-vocalized pulse, all four harmonics occur at the same time, so that it does not excite FMeFM neurons. However, when the animal itself emits a pulse, the FMeFM neurons are conditioned by the pulse FM1 to respond to echo FMn for processing target distance information. In this way, the neural processing of bio-sonar information is protected to great extent from the masking that would be caused by many bio-sonar pulses emitted by conspecifics (Suga and O'Neill, 1979). This hetero-harmonic sensitivity is one of eight mechanisms for the protection of biosonar signal processing (Suga et al., 1983). 9. Other specializations of FMeFM neurons 9.1. Frequency sweep sensitivity The responses of FM-sensitive or -selective (specialized) neurons, which are usually sensitive to the direction of a frequency sweep, have been explained by the sequence of stimulation of excitatory and inhibitory areas by a FM sweep or by a neural circuit incorporating disinhibition and/or facilitation (Suga, 1965b; Fuzessery, 1994; Fuzessery et al., 2011). Neurons with an excitatory area associated with an inhibitory area or sideband in the brainstem must be sensitive to the direction of frequency sweep. FM-selective neurons have been observed at the level of the inferior colliculus (little brown bats, Suga, 1969; mustached bats, O'Neill,

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1985; pallid bats, Fuzessery, 1994), and may be more common at higher levels (little brown bats, Suga, 1965a,b). In the inferior colliculus, all FMeFM neurons respond to single tone bursts. Twentyfive percent of them show no facilitative responses to paired tone bursts, but to paired FM sounds (Macias et al., 2012). Therefore, a frequency sweep is one of the important acoustic parameters for the facilitation of FMeFM neurons. The direction of the frequency sweep of a FM sound is important for the facilitative responses of many cortical FMeFM neurons. Their facilitative responses are larger to downward sweeping FM1eFMn pairs as in their biosonar signals than to upward sweeping unnatural sounds (Fig. 1D; Suga et al., 1983). The facilitative responses of ~10% of cortical FMeFM neurons disappear when FM1 of a FM1eFMn pair sweeps upward. Those of ~40% of the neurons disappear when FMn of the FM1eFMn pair sweeps upward. Therefore, FMeFM neurons show a specialization for responding to naturally occurring biosonar signals (Taniguchi et al., 1986). It remains to be studied whether collicular FMeFM neurons are sensitive to the direction of frequency sweep, as cortical ones are. 9.2. Doppler shifts and frequency axis A positive Doppler shift is important for the optimal facilitation of most FMeFM neurons, because the best FMn for facilitation is slightly higher than the harmonics of the best FM1 for facilitation; the initial frequency of a best FM for facilitation is 30.4, 61.6, 91.8 and 122.3 kHz for FM1e4 on the average. If the initial frequencies of best FM1 and FM2 of a given neuron are 30.4 and 61.6 kHz, respectively, it may be interpreted that the neuron is optimally excited by a Doppler-shifted echo of 0.8 kHz, which corresponds to a velocity of ~2.3 m/s, comparable to a bat's velocity in the approach phase of a target-directed flight. This does not mean that FMeFM neurons are also specialized for processing velocity information, but means that they are optimized to respond best to naturally occurring stimuli. The initial frequencies of the best FM1e4 for facilitation are very similar to the frequencies of CF1e4 components of a pulse and its echo. However, the essential component within the FM sound for facilitation is 27, 58, 88 and 110 kHz for FM1e4 on the average (Suga et al., 1983). The frequency tuning curves of FMeFM neurons for facilitation are broad (Olsen and Suga, 1991b). In the thalamus, there is another category of neurons, CF/CF neurons that are highly specialized for Doppler-shift analysis (Olsen and Suga, 1991a). The FF area in the auditory cortex has the frequency-versusfrequency coordinates in addition to the delay axis when studied with FMeFM stimuli (Misawa and Suga, 2001). So, the dorsal division of the medial geniculate body would be expected to have such coordinates. Wenstrup (1999) did not find a tonotopic (i.e., frequency) axis in the dorsal division when studied with single tone stimuli. It is essential to study the neurophysiological organization of this dorsal division with FMeFM stimuli, because FMeFM neurons are tuned to a specific combination of two FM sounds. 9.3. Spatial tuning When measured with a FM1eFMn pair at the best amplitudes or at 30 dB above minimum threshold for facilitation, FMeFM neurons have a very broad spatial auditory field for FMn, covering the entire contralateral auditory field or the entire contralateral and the medial half of the ipsilateral auditory field. A spatial auditory field for FM1 covers the entire auditory field. However, their spatial auditory fields at 10 dB above minimum threshold are small. Their best azimuths for facilitation are contralateral 35 for FM2 and contralateral 19 for FM3 and FM4, as those of the summated auditory nerve response (N1) to a tone burst. The best azimuth for

FM1 is contralateral 2 , which is quite different from the best azimuth, ipsilateral 25 , of N1 (Suga et al., 1990a). This FM1 directionality for facilitation is one of the adaptations of FMeFM neurons to be conditioned by FM1 of “non-directional” vocal selfstimulation to respond to FMn with a specific delay from it. 9.4. Responses to communication calls Mustached bats emit at least 33 types of communication calls. Unlike biosonar pulses, these calls contain an intense first harmonic at a frequency ranging from 8 to 30 kHz (Kanwal et al., 1994). Cortical FMeFM neurons show facilitative responses to several types of calls consisting of repetitive FM components or a train of FM sounds (Fig. 9AeC). A best call type for facilitative response is somewhat different between FMeFM neurons. FMeFM neurons responding to a call consisting of a train of FM sounds show a facilitative response to the second sound of the train (Fig. 9A). The best time interval between FM sounds within a train is ~10 times longer than the best echo delay measured with pulse-echo pairs (Ohlemiller et al., 1996). FMeFM neurons also respond to calls consisting of two or more FM sounds combined without an intervening silence interval (Fig. 9B and C; Esser et al., 1997). The response properties of FMeFM neurons dynamically change according to spectro-temporal patterns of acoustic signals, such as biosonar signals or communication calls. That is, their responses change according to differences in the combination of excitation and inhibition due to the spectro-temporal differences between acoustic signals. FMeFM neurons may play multiple roles in auditory signal processing (Suga, 1994). 10. Conclusions and future research Collicular FMeFM neurons project to thalamic ones, which in turn project to cortical ones. Therefore, the so-called basic response properties of FMeFM neurons in those three levels are similar to each other, as reported by Portfors and Wenstrup (1999, 2001, 2004), Wenstrup and Portfors (2011) and Macias et al. (2012). What is necessary for understanding auditory signal processing is to identify the differences in response properties between those three levels. A number of observations indicate that the thalamic and cortical FMeFM neurons are different from the collicular ones, and there are several findings made in the cortical auditory areas, but not in the inferior colliculus, as already described in this article. Those differences are summarized below. Compared with or different from collicular FMeFM neurons, thalamic and/or cortical FMeFM neurons show: (1) weak responses to individual acoustic stimuli, but strong responses to combinations of FM sounds (Taniguchi et al., 1986; Olsen and Suga, 1991b; Hagemann et al., 2011); (2) larger facilitation indexes when calculated with the data obtained “at the best amplitude for facilitation” (Yan and Suga, 1996a); (3) dramatically lower thresholds of facilitative responses to FMeFM stimuli than those of responses to single FM stimuli (Olsen and Suga, 1991b; Suga et al., 1983); (4) poorer level-tolerance (Macias et al., 2012); (5) sharper tuning to a specific combination of echo delay and echo amplitude (O'Neill and Suga, 1982; Suga et al., 1983); (6) a large inhibitory delay area following a facilitative delay-tuned area (Edamatsu and Suga, 1993); and (7) larger corticofugal modulation of delay tuning and facilitative response, indicating that sub-cortical facilitative responses greatly depend on corticofugal feedback (Yan and Suga, 1999). Several findings made in the auditory cortex, but not in the inferior colliculus, are summarized below. (1) Tracking (O'Neill and Suga, 1979, 1982) and multi-combination-sensitive neurons are found in the FF area (Misawa and Suga, 2001). (2) FMeFM neurons are clustered in three separate areas that are different in the length

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Fig. 9. Facilitative responses of cortical FMeFM neurons to communication calls. (AeC) The top panels show the oscillograms and spectrograms of calls. The lower panels (1e3 or 4) show PST histograms displaying responses of single neurons to the calls or part of the calls. (The call names were given by Kanwal et al., 1994). (A) Responses of a FM1eFM2 neuron with a 4.7 ms best delay to a call “dRFM” consisting of syllables 1 and/or 2 (Ohlemiller et al., 1996). (B) Responses of a FM1eFM2 neuron with a 6.0 ms best delay to a call consisting of “dRFM” and/or “cDFM”. (C) Responses of a FM1eFM3 neuron with a 6.4 ms best delay to a call consisting of “fSFM” and/or “bUFM” (Esser et al., 1997).

of delay axis (Suga and O'Neill, 1979; Suga and Horikawa, 1986; Edamatsu et al., 1989), neural response properties (Edamatsu and Suga, 1993), and connectivity (Fitzpatrick et al., 1998a). (3) FM1 and FMn responses are inhibited by FM1eFMn paired stimuli, if FMn delay from FM1 is shorter than the best delay of a given neuron (Suga et al., 1983; Edamatsu and Suga, 1993). (4) Most of FMeFM neurons have a facilitative delay-tuning curve sandwiched by inhibitory regions (Edamatsu and Suga, 1993). (5) Delay-widths measured with double echoes are narrower than those measured with a single echo. The amount of narrowing is larger in the VF area than in the FF area (Edamatsu and Suga, 1993). (6) The facilitative responses of neurons in the VF area adapt quickly for repetitive stimuli with a FM1eFMn pair (Edamatsu and Suga, 1993). FMeFM neurons in the VF area are quite different from those in the inferior colliculus. (7) Delay tuning of cortical FMeFM neurons is improved and adjusted by cortico-cortical interactions consisting of positive feedback associated with lateral inhibition (Xiao and Suga, 2004; Tang et al., 2007; Tang and Suga, 2008, 2009). (8) In general, plasticity in tuning properties elicited by fear conditioning or cortical electric stimulation is long lasting in the auditory cortex but short lasting in the inferior colliculus (Suga, 2012). These observations enumerated above indicate that the auditory system is a neural net for hierarchical signal processing. The following topics may be enumerated for further research.

(1) Models for modulation

delay-tuned

facilitation

and

corticofugal

Cortical FMeFM neurons show amplitude tuning and FM selectivity, in addition to delay tuning (Suga et al., 1983). Cortical FMeFM neurons respond to certain types of communication calls (Ohlemiller et al., 1996). Cortical FMeFM neurons interact with each other for adjustment and improvement of their response properties. Activation or inactivation of cortical FMeFM neurons drastically changes the response properties of collicular FMeFM neurons (Yan and Suga, 1996b, 1999; Tang and Suga, 2009). The neural nets for the response properties and neural interactions summarized above should be incorporated into the models for delay-tuned facilitation. In particular, the neural circuit and synaptic mechanisms for the delay-tuned facilitation of FMeFM neurons should be re-considered by adding corticofugal feedback to the over-simplified models shown in Fig. 3. (2) Delay-tuned facilitation and NMDA receptors Unpublished data obtained by Butman (1992) indicate that thalamic FMeFM neurons show facilitative responses mediated by both non-NMDA and NMDA receptors, and that their facilitative responses are modified by GABA-A-mediated inhibition. His

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findings remain to be re-examined. In addition, the roles of NMDA and GABA receptors should be studied in relation to cortical distance information processing. Systematic research remains to be performed for further exploration of hierarchical auditory signal processing. (3) Multiple representations of echo delays In the auditory cortex, FMeFM neurons are clustered in the FF, DF and VF areas (Suga and Horikawa, 1986; Edamatsu et al., 1989; Fitzpatrick et al., 1998b). The neurophysiological differences between these three areas remain to be further explored, under increasingly realistic situations with multiple echo sources. The behavioral relevance of those three areas also remains to be studied. (4) Change in response properties due to spectro-temporal differences in acoustic signals The response properties of FMeFM neurons change depending on whether a stimulus is a pulse-echo pair or a communication call (Ohlemiller et al., 1996). The essential components of the communication call for their facilitative responses remain to be identified, and how the combination of excitation and inhibition changes due to the spectro-temporal differences between acoustic stimuli should be studied. (5) Stimulus design and non-linearity of neural responses In “single unit” auditory neurophysiology, exploration of the response properties of a neuron is limited by acoustical stimuli delivered to an animal. Therefore, we should carefully design acoustic stimuli and data acquisition and processing, considering the response properties of a given neuron. For example, the superior colliculus contains “3D” neurons tuned to a specific combination of distance (echo delay), azimuth and elevation (Valentine and Moss, 1997). Such finding was made only by changing azimuth and elevation of a loudspeaker in addition to echo delay. The location of a loudspeaker delivering acoustic stimuli should be determined, considering whether the stimuli should be delivered to stimulate both the ears equally or one ear predominantly according to the aims of research. The response magnitude and pattern of central auditory neurons change nonlinearly with stimulus levels. Therefore, data acquisition and processing should be designed, considering the nonlinearity of neural responses. The data obtained at 10 dB above minimum threshold can be different from those obtained at best amplitudes to which neurons are tuned, as already described in the current article. One should know that “for convenience”, Kiang et al. (1965) measured the width of a neural frequency-tuning curve at 10 dB above minimum threshold to express its sharpness by a Q10 dB value. That is, one should know that Q-10 dB was defined on an arbitrary basis without any consideration of whether it expressed best the sharpness of the neural tuning curve. Acknowledgments The author is greatful to Drs. David E. Crowley and Kevin K. Ohlemiller for their comments on the current article, and to his wonderful collaborators for their research in his laboratory at Washington University. References Bodenhamer, R.D., Pollak, G.D., 1981. Time and frequency domain processing in the inferior colliculus of echolocating bats. Hear. Res. 5, 317e335.

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