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Impaired executive function following ischemic stroke in the rat medial prefrontal cortex
Behavioural Brain Research 258 (2014) 106–111
Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Research report
Impaired executive function following ischemic stroke in the rat medial prefrontal cortex Chris A. Cordova a,b , Danielle Jackson a , Kristopher D. Langdon a,b , Krista A. Hewlett a , Dale Corbett a,b,c,d,∗ a
Division of BioMedical Sciences, Memorial University, St. John’s, NL, Canada Heart and Stroke Foundation Centre for Stroke Recovery, Canada c Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada d Department of Medicine, University of Toronto, Toronto, ON, Canada b
h i g h l i g h t s • We describe a rodent model of executive dysfunction. • Bilateral prefrontal cortical ischemia induces executive dysfunction. • Mediodorsal thalamic ischemia does not impair executive function in young animals.
a r t i c l e
i n f o
Article history: Received 23 July 2013 Received in revised form 6 October 2013 Accepted 11 October 2013 Available online 19 October 2013 Keywords: Attention set-shifting Executive function Mediodorsal thalamus Prefrontal cortex Rat
a b s t r a c t Small (lacunar) infarcts frequently arise in frontal and midline thalamic regions in the absence of major stroke. Damage to these areas often leads to impairment of executive function likely as a result of interrupting connections of the prefrontal cortex. Thus, patients experience frontal-like symptoms such as impaired ability to shift ongoing behavior and attention. In contrast, executive dysfunction has not been demonstrated in rodent models of stroke, thereby limiting the development of potential therapies for human executive dysfunction. Male Sprague-Dawley rats (n = 40) underwent either sham surgery or bilateral endothelin-1 injections in the mediodorsal nucleus of the thalamus or in the medial prefrontal cortex. Executive function was assessed using a rodent attention set shifting test that requires animals to shift attention to stimuli in different stimulus dimensions. Medial prefrontal cortex ischemia impaired attention shift performance between different stimulus dimensions while sparing stimulus discrimination and attention shifts within a stimulus dimension, indicating a selective attention set-shift deficit. Rats with mediodorsal thalamic lacunar damage did not exhibit a cognitive impairment relative to sham controls. The selective attention set shift impairment observed in this study is consistent with clinical data demonstrating selective executive disorders following stroke within specific sub-regions of frontal cortex. These data contribute to the development and validation of a preclinical animal model of executive dysfunction, that can be employed to identify potential therapies for ameloriating cognitive deficits following stroke. © 2013 Elsevier B.V. All rights reserved.
1. Introduction
Abbreviations: CD, compound discrimination; ED, extradimensional shift; ID, intradimensional shift; LI, learned irrelevance; MD, mediodorsal thalamus; PFC, prefrontal cortex; REV, reversal; SD, simple discrimination; WCST, Wisconsin Card Sorting Test. ∗ Corresponding author at: Department of Cellular & Molecular Medicine, Roger Guindon Hall, Room 3510G, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5. Tel.: +1 613 562 5800x8177; fax: +1 613 562 5622. E-mail address: [email protected] (D. Corbett). 0166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2013.10.022
Vascular disease is the most common cause of frontal lobe and subcortical dementias, and may account for up to 25% of degenerative dementias among middle-aged individuals [1]. Ischemic brain damage in the prefrontal cortex (PFC) caused by progressive atherosclerosis or embolism often lead to impairments in executive function, including problems with planning, behavioral flexibility and attention set shifting ability [2–5]. Cognitive impairment can result from either large or small vessel disease. Unlike large vessel stroke, small vessel disease typically does not include obvious sensory-motor or behavioral symptoms and are thus called
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Table 1 Order of discriminations. Discrimination
Relevant dimension
Irrelevant dimensions
Simple discrimination (SD) Compound discrimination (CD) Intradimensional shift (ID) Reversal 1 (Rev 1) Extradimensional shift (ED) Reversal 2 (Rev 2) Learned irrelevance (LI)
Odor (patchouli) Odor (patchouli) Odor (nutmeg) Odor (lavender) External texture (furry) External texture (flat) External texture (flat)
External texture & digging medium External texture & digging medium External texture & digging medium Odor & digging medium Odor & digging medium (yellow paper) Odor & digging medium (blue paper)
Examples of stimulus combinations are shown for a rat shifting attention from odor to external texture. The attention set shift test is comprised of seven discriminations where a relevant cue is associated with a hidden reward. The discriminations include simple (SD) and compound discriminations (CD), an interdimensional attention shift (ID) to stimuli within the same dimension as the previous discriminations (e.g. odor), and a reversal (REV1) to the previously unrewarded stimulus of the same dimension. Subsequently, an extradimensional attention shift (ED) is made to a stimulus in a new dimension (e.g. external texture), followed by a second reversal and a test of learned irrelevance.
silent or covert strokes, but they often lead to selective impairments of executive cognitive function [6,7]. Patients with large vessel stroke or small vessel disease frequently exhibit a strikingly similar pattern of impairments in frontal cortex-dependent tasks such as the Trail Making test and the Wisconsin Card Sorting Test (WCST) which respectively assess abilities to shift behavioral tasks and attention [8,9]. Small vessel disease also commonly results in lacunar infarcts in midline thalamic structures within watershed areas that are highly susceptible to hypoperfusion [10]. Thus the predominance of frontal symptoms arising from medial thalamic stroke has been proposed to result from damage to the mediodorsal (MD) thalamic nucleus that provides the major input to PFC, and the subsequent interruption of frontal-subcortical circuits [11,12]. Covert stroke occurs five times more frequently than clinically evident overt strokes [6] and cerebral infarctions resulting from covert stroke have been found in 23–33% of unaware, apparently healthy middle-aged adults [7,11]. While the symptoms of covert stroke may initially be subtle, covert stroke greatly increases the risk of subsequent overt stroke and often leads to the development of vascular dementia [6] which is characterized by impairments in attention and executive function [12,13]. In view of the very high incidence and long-term costs associated with stroke related cognitive impairment it would be useful to develop an animal model of executive dysfunction arising from ischemic damage in either the PFC or MD since cognition is often not assessed in preclinical stroke studies [14,15]. To address these concerns, this study used an animal model of attention set shifting to investigate the cognitive effects of ischemic infarcts within the rodent mediodorsal thalamic nuclei or medial prefrontal cortex, an area that makes analogous connections to the human dorsolateral prefrontal cortex. Consistent with human findings, we hypothesized that ischemic damage in either the MPFC or MD would selectively impair the ability to shift attention between different feature sets of stimuli while sparing other aspects of attention and learning.
2. Materials and methods 2.1. Subjects Forty, 3–5 month old male Sprague-Dawley rats (Charles River Laboratories, Montreal, Quebec, Canada) weighing ∼450–600 g at time of behavioral testing were used in this experiment. Animals were housed on a reverse 12 h light/dark cycle with food and water ad libitum. Behavioral assessments were conducted during the dark phase. All procedures adhered to guidelines established by the Canadian Council on Animal Care and received prior approval from the Institutional Animal Care Committee of Memorial University.
2.2. Surgery After socialization and habituation to the testing environment, ischemia was induced under isoflurane anesthesia (4.0% induction, 2.0% maintenance in 100% O2 ). Animals were placed in a stereotaxic frame, with a flat head angle, and bilateral injections of the vasoconstrictive peptide, endothelin-1 (ET-1), were infused into the MD (n = 14) or the PFC (n = 13). The PFC encompasses prelimbic, infralimbic and anterior cingulate cortex, which receive afferents from MD [8] and has been implicated in attention set shifting ability in rodents [16,17]. Sham animals underwent similar surgical procedures with burr holes drilled in corresponding frontal or thalamic coordinates (n = 13). Temperature was maintained at ∼37 ◦ C throughout surgery using a self-regulating heating blanket (Harvard Apparatus, Holliston, MA, USA). In the PFC, four sites were infused with 0.8 L ET-1 at the following coordinates [16]: anterior–posterior (AP) +3.5 mm from bregma, medio-lateral (ML) ±0.6 mm, dorso-ventral (DV) −5.2 mm; AP +2.5 mm, ML ±0.6 mm, DV −5.0 mm. Ischemia was induced in the MD by bilateral infusions of 0.25 L ET-1 at coordinates AP −2.8 mm, ML ±0.7 mm, DV −5.8 mm. Functional assessments commenced 10 days following recovery from surgery by an experimenter blinded to experimental condition. 2.3. Behavioral training Rats were mildly food restricted to 90% of their free-feeding weight and trained to make a series of discriminations between stimuli by finding a hidden 1/3 Honey Nut Cheerio© (General Mills, Mississauga, ON, Canada) food reward buried in one of two 10 cm diameter ceramic pots in which the location was consistently paired with one of two different stimuli (see below). Criterion for successful discrimination consisted of the rat digging with its paws or nose in the pot containing the buried reward on six consecutive trials. Three subjects were excluded for failure to complete this criterion. The attention set shift test was administered the following day and consisted of seven discriminations (Table 1) [18]: (1) a simple discrimination (SD) where rats were rewarded for responding to a stimulus feature of one of the two pots (e.g. a patchouli odor) using simplified pots with features added only in one relevant stimulus dimension (e.g. odors); (2) a compound discrimination (CD) where the reward was paired with the same stimulus feature in complex pots where two additional, irrelevant, stimulus dimensions were added (e.g. different digging media and external textures); (3) an interdimensional shift (ID), where a new set of pots were presented (Table 2) and the rat was required to locate the reward paired with one of two features in the same sensory dimension as the previous tests (e.g. a nutmeg odor); (4) a reversal (REV1), where the other, previously unrewarded feature in the same sensory dimension was
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Table 2 Example test stimuli. Pair 1
Odor Medium Texture
Pair 2
Pair 3
1
2
3
4
5
6
Patchouli Textured color metal Rough cardboard
Cinnamon Round silver metal Smooth cardboard
Nutmeg White plastic beads Terrycloth pile
Jasmine Color plastic beads Reversed terrycloth
Orange Yellow paper Furry fabric
Lavender Blue paper Reversed fur fabric
During each discrimination, a stimulus feature of one of two pots was consistently paired with a buried reward (e.g. patchouli odor). In the ID, new stimuli were presented (Pair 2) and a feature in the same stimulus dimension was rewarded (e.g. nutmeg odor). In the ED, new stimuli were presented again (Pair 3) and a feature in a previously unrewarded dimension was rewarded (e.g. furry external texture).
rewarded (e.g. a jasmine odor; a test of perseveration). The fifth and critical test for assessing executive function was an extradimensional shift (ED), where a new set of pots were presented (Table 2) and the reward was paired with a feature in a new sensory dimension (e.g. fur on the outside of a pot), which required a shift of attention from the previously rewarded stimulus dimension (odor) to a new dimension (external texture); (6) this was followed by a second reversal (REV2) within this new dimension (e.g. external texture; another assessment of perseveration); (7) and a learned irrelevance test (LI) where a change was made in the third sensory dimension which had never been varied or rewarded during the test (e.g. the digging medium) while keeping the reward cue the same (i.e. external texture), thus assessing rats’ ability to ignore irrelevant stimuli, an important aspect of attentional processing [19]. The sensory dimensions of ED attention shifts were balanced across rats. 2.4. Tissue processing Following testing, animals were deeply anesthetized with 4.0% isoflurane, transcardially perfused with ice-cold 0.9% heparinized
saline and 4.0% paraformaldehyde (PFA). Brains were removed and stored overnight in PFA at 4 ◦ C and then transferred to 20% sucrose in phosphate-buffered saline and stored at 4 ◦ C until saturated. Coronal slices were cut at 20 m with a cryostat, stained with cresyl violet and examined for needle placement and lesion size by an experimenter who was blinded to experimental conditions. To calculate PFC infarct volume (ImageJ 1.36b software, National Institutes of Health), sections were measured at 400 m intervals throughout the frontal lobes from bregma +5 mm AP to −1 mm AP, and the infarct volume was calculated as: (the average area of remaining damaged tissue in each section) × (number of sections analyzed) × (distance between sections) [20]. Because of the bilateral nature of damage, the contralateral hemisphere could not be used as a control, therefore the measured volume does not account for lost, shrunken or replaced tissue. Evident gliosis within the MD was taken as a measure of injury since the small injections of ET-1 created lacunar-like injury rather than frank infarcts. To calculate MD gliosis volume, sections were measured at 80 m intervals throughout the thalamus and volume was calculated as (average area of gliosis within MD) × (number of sections analyzed) × (distance between sections).
Fig. 1. Representative injury profile of animals with bilateral ischemic damage in the (A) prefrontal cortex (13.7 ± 3.7 mm3 (mean ± SEM)) and (B) evident gliosis in the mediodorsal thalamus (0.404 ± 0.063 mm3 (mean ± SEM)). Areas depicted are maximum (light gray), minimum (black) and median (dark gray) extent of ET-1 injury. Brain sections adapted from Paxinos and Watson (numbers correspond to millimeters from bregma) [39].
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Fig. 2. Mean number of trials to criterion (±SEM) on the attention set shift tests. Ischemic PFC rats required significantly more trials to criterion than sham subjects on the extradimensional (ED) shift, indicating an impairment in the ability to shift attention to a new stimulus dimension (*p < 0.05). There were no differences among ischemic groups in the performance of the interdimensional shift (ID), simple and compound discriminations (SD and CD), reversals (REV1 and REV2) and the test of learned irrelevance (LI).
2.5. Statistical analysis A series of univariate analysis of variances (ANOVA) were used to assess the effects of ischemia in MD and PFC on acquisition, reversals, attention shifts and learned irrelevance. Tukey’s honestly significant difference criterion was used for multiple comparisons. A subsequent Pearson product-moment correlation coefficient was calculated in order to assess the relationship between functional deficit and volume of ischemic damage. Statistical significance was considered at p ≤ 0.05.
p = 0.329) or the test of learned irrelevance (ED: F2,30 = 0.37, p = 0.693) (Fig. 2). 3.3. Relationship between PFC infarct and functional deficit A Pearson product-moment correlation between PFC infarct volume and ED performance did not reach statistical significance (r = 0.51, p > 0.05), although there was a positive relationship between these variables, with 26% of the variance explained by lesion volume alone (Fig. 3).
3. Results
4. Discussion
3.1. Infarct assessment
The current study investigated the effects of ischemic damage within the PFC and MD on executive cognitive function. Ischemic damage to medial prefrontal cortex resulted in a selective impairment in the ability to shift attention between stimulus dimensions, the ED shift. However, rats with PFC damage did not differ from control groups in any other measures used in the test, indicating a selective dysfunction in shifting attention set and not in
ET-1 injections in prefrontal cortex created ischemic infarcts that had an average volume of 13.7 ± 3.7 mm3 (mean ± SEM) and typically included prelimbic, infralimbic and anterior cingulate cortex (Fig. 1A). One subject was excluded for inadequate lesion size (<4 mm3 ). Mediodorsal thalamic damage was more difficult to quantify due to the relatively small amounts of ET-1 injected (0.25 L) and the length of time before sacrifice. However, in order to quantify the injury, we calculated the volume of evident MD gliosis. On average, animals displayed gliosis measuring 0.404 ± 0.063 mm3 (mean ± SEM) in each MD nucleus (Fig. 1B). Animals were included in the behavioral analyses only if bilateral damage (i.e. evident gliosis) was noted within the MD. All animals (n = 14) met this criterion. 3.2. Behavioral analysis An ANOVA of the extradimensional attention shifts revealed a significant effect of Lesion on performance (ED: F2,30 = 5.32, p = 0.011; Fig. 2). Rats with PFC damage required significantly more trials to reach criterion performance relative to sham-lesion controls on tests when attention shifted between stimulus dimensions (ED) (p < 0.05); but not when the attention shifts were maintained within a stimulus dimension (ID) (p > 0.05; Fig. 2). In contrast, MD rats did not significantly differ from sham-lesion rats on either the ED (p > 0.05) or ID (p > 0.05). Consistent with our hypothesis, PFC or MD infarcts did not affect performance acquisition (SD: F2,30 = 1.42, p = 0.258, CD: F2,30 = 0.27, p = 0.767), reversals (REV1: F2,30 = 0.03, p = 0.970, REV2: F2,30 = 1.15,
Fig. 3. Scatter plot with line of best fit demonstrating the relationship between prefrontal cortex (PFC) infarct volume (mm3 ) and functional deficit in the extradimensional (ED) shift. Although positive, the Pearson product-moment correlation failed to reach statistical significance (p > 0.05).
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acquisition, attention shifting or perseveration. Further, ischemic lesions of the MD did not impair performance in any of the measures of attention shifting compared to sham surgery. The results of the current study are the first demonstration that an impairment of executive function can arise from a rodent model of ischemic stroke within the PFC. Critically, these findings closely parallel the selective impairment of set shifting ability of humans in the WCST following stroke in the dorsolateral region of the prefrontal cortex, an area thought to be homologous to the rodent PFC [2–5,21]. Although there was a positive relationship, the fact that there was no significant correlation between PFC infarct volume and ED performance leads one to speculate that location of ischemic damage is a greater contributor to this functional deficit than overall infarct volume. In this study, bilateral lesions were used to model human impairments that commonly arise from unilateral damage in the PFC [22] or MD [9]. Because human executive cognitive function is much more lateralized than rodent brain function [23,24] robust cognitive impairments result from unilateral stroke in humans. In rodents however, bilateral injury is commonly induced [25,26] and was validated in the current study to create cognitive impairments of a similar magnitude as would occur in humans [21,27]. Our results are also similar to previous findings of set shifting impairments in rats following excitotoxic lesions of PFC [16]. Contrary to our hypothesis, damage to the MD did not produce deficits in the ED shift of the attention set shifting test. It is possible that the lesions to MD (0.404 mm3 ) were not sufficiently large enough to disrupt attentional processing in the PFC or that afferents from the MD are not necessary for attention set shifting in rodents. However, this latter hypothesis is unlikely because deficits in behavioral strategy shifting are prominent following bilateral infusions of 0.5 L bupivicaine into MD nucleus of rats [24]. Because of differences in drug mechanisms of action and outcomes, it is impossible to directly compare the current results, however, that study [24] demonstrated an integral role of the MD in rodent executive functioning. Other inactivation and lesion studies in rats further highlight the importance of the MD thalamus in higher-order cognitive functioning [28,29]. Therefore, slightly larger areas of damage in the MD may be required in order to precipitate executive dysfunction. These data should be considered in future studies of ischemia-induced executive dysfunction targeting the MD nucleus. Cognitive impairment has been proposed to arise from several types of vascular lesions including single or multiple infarcts, chronic hypoperfusion and white matter damage, also referred to as leukoaraiosis [30]. While these lesions can affect the prefrontal circuitry including the PFC and MD, they may also damage axon tracts in subcortical structures that were not investigated in the current study. For example, the volume of MRI white matter injury (i.e. hyperintensities) resulting from hypoperfusion is higher in the prefrontal region than in other cortical regions [31]. Patients with both lacunar infarcts and cognitive decline have more white matter lesions in the frontal lobes whose severity correlates with executive dysfunction [32,33]. Further, patients with multiple cerebral infarcts have lower perfusion rates and metabolic activity in frontal cortex [34] correlating with reduced executive function [35]. These types of insults are important contributors to cognitive dysfunction in humans, but are difficult to model preclinically. Nonetheless, the data obtained in the current study, represent the first steps in developing an animal model of ischemia-induced executive dysfunction. Cognitive impairments are often overlooked in preclinical studies [36], but can be very devastating to patients and families [37]. Further development of animal models to assess interventional therapies for ‘frontal-syndrome’ deficits will be an instrumental step in counteracting stroke associated executive dysfunction.
In conclusion, the present data represent an animal model of prefrontal stroke characterized by profound executive dysfunction. In accordance with the STAIR recommendations [38], future inclusion of co-morbid conditions will further increase the clinical relevancy of these models. Co-morbid conditions such as advanced age, hypertension, and inflammation may alter functional properties of frontal cortex and associated neural networks that in turn may further exacerbate the cognitive impairments observed in the present study. The incorporation of co-morbid variables will increase the probability of translation to the clinical population. Acknowledgements This research was supported by an operating grant from the Canadian Stroke Network (DC). KDL was supported by a studentship from the Canadian Stroke Network. The authors thank Shirley Granter-Button for technical assistance and helpful comments on the manuscript. References [1] Roman GC. Vascular dementia: distinguishing characteristics, treatment, and prevention. J Am Geriatr Soc 2003;51:S296–304. [2] Stuss DT, Levine B, Alexander MP, Hong J, Palumbo C, Hamer L, et al. Wisconsin Card Sorting Test performance in patients with focal frontal and posterior brain damage: effects of lesion location and test structure on separable cognitive processes. Neuropsychologia 2000;38:388–402. [3] Barcelo F, Knight RT. Both random and perseverative errors underlie WCST deficits in prefrontal patients. Neuropsychologia 2002;40:349–56. [4] Pohjasvaara T, Leskela M, Vataja R, Kalska H, Ylikoski R, Hietanen M, et al. Poststroke depression, executive dysfunction and functional outcome. Eur J Neurol 2002;9:269–75. [5] Ravizza SM, Ciranni MA. Contributions of the prefrontal cortex and basal ganglia to set shifting. J Cognitive Neurosci 2002;14:472–83. [6] Vermeer SE, Longstreth Jr WT, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007;6:611–9. [7] Longstreth Jr WT, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 1998;55:1217–25. [8] Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873–80. [9] Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HB, Jolles J. Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 2003;41:1330–44. [10] Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1:426–36. [11] Carey CL, Kramer JH, Josephson SA, Mungas D, Reed BR, Schuff N, et al. Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke 2008;39:397–402. [12] O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurol 2003;2:89–98. [13] Jokinen H, Kalska H, Mantyla R, Pohjasvaara T, Ylikoski R, Hietanen M, et al. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosur Psychiatry 2006;77:28–33. [14] Taghibiglou C, Martin HG, Lai TW, Cho T, Prasad S, Kojic L, et al. Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med 2009;15:1399–406. [15] Simard JM, Yurovsky V, Tsymbalyuk N, Melnichenko L, Ivanova S, Gerzanich V. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke 2009;40:604–9. [16] Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 2000;20:4320–4. [17] Barense MD, Fox MT, Baxter MG. Aged rats are impaired on an attentional setshifting task sensitive to medial frontal cortex damage in young rats. Learn Mem 2002;9:191–201. [18] McGaughy J, Ross RS, Eichenbaum H. Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 2008;153:63–71. [19] Holland PC, Bouton ME. Hippocampus and context in classical conditioning. Curr Opin Neurobiol 1999;9:195–202. [20] Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM. Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000;20:1702. [21] Anderson SW, Damasio H, Jones RD, Tranel D. Wisconsin Card Sorting Test performance as a measure of frontal lobe damage. J Clin Exp Neuropsychol 1991;13:909–22. [22] Zinn S, Bosworth HB, Hoenig HM, Swartzwelder HS. Executive function deficits in acute stroke. Arch Phys Med Rehabil 2007;88:173–80.
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Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Research report
Impaired executive function following ischemic stroke in the rat medial prefrontal cortex Chris A. Cordova a,b , Danielle Jackson a , Kristopher D. Langdon a,b , Krista A. Hewlett a , Dale Corbett a,b,c,d,∗ a
Division of BioMedical Sciences, Memorial University, St. John’s, NL, Canada Heart and Stroke Foundation Centre for Stroke Recovery, Canada c Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada d Department of Medicine, University of Toronto, Toronto, ON, Canada b
h i g h l i g h t s • We describe a rodent model of executive dysfunction. • Bilateral prefrontal cortical ischemia induces executive dysfunction. • Mediodorsal thalamic ischemia does not impair executive function in young animals.
a r t i c l e
i n f o
Article history: Received 23 July 2013 Received in revised form 6 October 2013 Accepted 11 October 2013 Available online 19 October 2013 Keywords: Attention set-shifting Executive function Mediodorsal thalamus Prefrontal cortex Rat
a b s t r a c t Small (lacunar) infarcts frequently arise in frontal and midline thalamic regions in the absence of major stroke. Damage to these areas often leads to impairment of executive function likely as a result of interrupting connections of the prefrontal cortex. Thus, patients experience frontal-like symptoms such as impaired ability to shift ongoing behavior and attention. In contrast, executive dysfunction has not been demonstrated in rodent models of stroke, thereby limiting the development of potential therapies for human executive dysfunction. Male Sprague-Dawley rats (n = 40) underwent either sham surgery or bilateral endothelin-1 injections in the mediodorsal nucleus of the thalamus or in the medial prefrontal cortex. Executive function was assessed using a rodent attention set shifting test that requires animals to shift attention to stimuli in different stimulus dimensions. Medial prefrontal cortex ischemia impaired attention shift performance between different stimulus dimensions while sparing stimulus discrimination and attention shifts within a stimulus dimension, indicating a selective attention set-shift deficit. Rats with mediodorsal thalamic lacunar damage did not exhibit a cognitive impairment relative to sham controls. The selective attention set shift impairment observed in this study is consistent with clinical data demonstrating selective executive disorders following stroke within specific sub-regions of frontal cortex. These data contribute to the development and validation of a preclinical animal model of executive dysfunction, that can be employed to identify potential therapies for ameloriating cognitive deficits following stroke. © 2013 Elsevier B.V. All rights reserved.
1. Introduction
Abbreviations: CD, compound discrimination; ED, extradimensional shift; ID, intradimensional shift; LI, learned irrelevance; MD, mediodorsal thalamus; PFC, prefrontal cortex; REV, reversal; SD, simple discrimination; WCST, Wisconsin Card Sorting Test. ∗ Corresponding author at: Department of Cellular & Molecular Medicine, Roger Guindon Hall, Room 3510G, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5. Tel.: +1 613 562 5800x8177; fax: +1 613 562 5622. E-mail address: [email protected] (D. Corbett). 0166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2013.10.022
Vascular disease is the most common cause of frontal lobe and subcortical dementias, and may account for up to 25% of degenerative dementias among middle-aged individuals [1]. Ischemic brain damage in the prefrontal cortex (PFC) caused by progressive atherosclerosis or embolism often lead to impairments in executive function, including problems with planning, behavioral flexibility and attention set shifting ability [2–5]. Cognitive impairment can result from either large or small vessel disease. Unlike large vessel stroke, small vessel disease typically does not include obvious sensory-motor or behavioral symptoms and are thus called
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Table 1 Order of discriminations. Discrimination
Relevant dimension
Irrelevant dimensions
Simple discrimination (SD) Compound discrimination (CD) Intradimensional shift (ID) Reversal 1 (Rev 1) Extradimensional shift (ED) Reversal 2 (Rev 2) Learned irrelevance (LI)
Odor (patchouli) Odor (patchouli) Odor (nutmeg) Odor (lavender) External texture (furry) External texture (flat) External texture (flat)
External texture & digging medium External texture & digging medium External texture & digging medium Odor & digging medium Odor & digging medium (yellow paper) Odor & digging medium (blue paper)
Examples of stimulus combinations are shown for a rat shifting attention from odor to external texture. The attention set shift test is comprised of seven discriminations where a relevant cue is associated with a hidden reward. The discriminations include simple (SD) and compound discriminations (CD), an interdimensional attention shift (ID) to stimuli within the same dimension as the previous discriminations (e.g. odor), and a reversal (REV1) to the previously unrewarded stimulus of the same dimension. Subsequently, an extradimensional attention shift (ED) is made to a stimulus in a new dimension (e.g. external texture), followed by a second reversal and a test of learned irrelevance.
silent or covert strokes, but they often lead to selective impairments of executive cognitive function [6,7]. Patients with large vessel stroke or small vessel disease frequently exhibit a strikingly similar pattern of impairments in frontal cortex-dependent tasks such as the Trail Making test and the Wisconsin Card Sorting Test (WCST) which respectively assess abilities to shift behavioral tasks and attention [8,9]. Small vessel disease also commonly results in lacunar infarcts in midline thalamic structures within watershed areas that are highly susceptible to hypoperfusion [10]. Thus the predominance of frontal symptoms arising from medial thalamic stroke has been proposed to result from damage to the mediodorsal (MD) thalamic nucleus that provides the major input to PFC, and the subsequent interruption of frontal-subcortical circuits [11,12]. Covert stroke occurs five times more frequently than clinically evident overt strokes [6] and cerebral infarctions resulting from covert stroke have been found in 23–33% of unaware, apparently healthy middle-aged adults [7,11]. While the symptoms of covert stroke may initially be subtle, covert stroke greatly increases the risk of subsequent overt stroke and often leads to the development of vascular dementia [6] which is characterized by impairments in attention and executive function [12,13]. In view of the very high incidence and long-term costs associated with stroke related cognitive impairment it would be useful to develop an animal model of executive dysfunction arising from ischemic damage in either the PFC or MD since cognition is often not assessed in preclinical stroke studies [14,15]. To address these concerns, this study used an animal model of attention set shifting to investigate the cognitive effects of ischemic infarcts within the rodent mediodorsal thalamic nuclei or medial prefrontal cortex, an area that makes analogous connections to the human dorsolateral prefrontal cortex. Consistent with human findings, we hypothesized that ischemic damage in either the MPFC or MD would selectively impair the ability to shift attention between different feature sets of stimuli while sparing other aspects of attention and learning.
2. Materials and methods 2.1. Subjects Forty, 3–5 month old male Sprague-Dawley rats (Charles River Laboratories, Montreal, Quebec, Canada) weighing ∼450–600 g at time of behavioral testing were used in this experiment. Animals were housed on a reverse 12 h light/dark cycle with food and water ad libitum. Behavioral assessments were conducted during the dark phase. All procedures adhered to guidelines established by the Canadian Council on Animal Care and received prior approval from the Institutional Animal Care Committee of Memorial University.
2.2. Surgery After socialization and habituation to the testing environment, ischemia was induced under isoflurane anesthesia (4.0% induction, 2.0% maintenance in 100% O2 ). Animals were placed in a stereotaxic frame, with a flat head angle, and bilateral injections of the vasoconstrictive peptide, endothelin-1 (ET-1), were infused into the MD (n = 14) or the PFC (n = 13). The PFC encompasses prelimbic, infralimbic and anterior cingulate cortex, which receive afferents from MD [8] and has been implicated in attention set shifting ability in rodents [16,17]. Sham animals underwent similar surgical procedures with burr holes drilled in corresponding frontal or thalamic coordinates (n = 13). Temperature was maintained at ∼37 ◦ C throughout surgery using a self-regulating heating blanket (Harvard Apparatus, Holliston, MA, USA). In the PFC, four sites were infused with 0.8 L ET-1 at the following coordinates [16]: anterior–posterior (AP) +3.5 mm from bregma, medio-lateral (ML) ±0.6 mm, dorso-ventral (DV) −5.2 mm; AP +2.5 mm, ML ±0.6 mm, DV −5.0 mm. Ischemia was induced in the MD by bilateral infusions of 0.25 L ET-1 at coordinates AP −2.8 mm, ML ±0.7 mm, DV −5.8 mm. Functional assessments commenced 10 days following recovery from surgery by an experimenter blinded to experimental condition. 2.3. Behavioral training Rats were mildly food restricted to 90% of their free-feeding weight and trained to make a series of discriminations between stimuli by finding a hidden 1/3 Honey Nut Cheerio© (General Mills, Mississauga, ON, Canada) food reward buried in one of two 10 cm diameter ceramic pots in which the location was consistently paired with one of two different stimuli (see below). Criterion for successful discrimination consisted of the rat digging with its paws or nose in the pot containing the buried reward on six consecutive trials. Three subjects were excluded for failure to complete this criterion. The attention set shift test was administered the following day and consisted of seven discriminations (Table 1) [18]: (1) a simple discrimination (SD) where rats were rewarded for responding to a stimulus feature of one of the two pots (e.g. a patchouli odor) using simplified pots with features added only in one relevant stimulus dimension (e.g. odors); (2) a compound discrimination (CD) where the reward was paired with the same stimulus feature in complex pots where two additional, irrelevant, stimulus dimensions were added (e.g. different digging media and external textures); (3) an interdimensional shift (ID), where a new set of pots were presented (Table 2) and the rat was required to locate the reward paired with one of two features in the same sensory dimension as the previous tests (e.g. a nutmeg odor); (4) a reversal (REV1), where the other, previously unrewarded feature in the same sensory dimension was
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Table 2 Example test stimuli. Pair 1
Odor Medium Texture
Pair 2
Pair 3
1
2
3
4
5
6
Patchouli Textured color metal Rough cardboard
Cinnamon Round silver metal Smooth cardboard
Nutmeg White plastic beads Terrycloth pile
Jasmine Color plastic beads Reversed terrycloth
Orange Yellow paper Furry fabric
Lavender Blue paper Reversed fur fabric
During each discrimination, a stimulus feature of one of two pots was consistently paired with a buried reward (e.g. patchouli odor). In the ID, new stimuli were presented (Pair 2) and a feature in the same stimulus dimension was rewarded (e.g. nutmeg odor). In the ED, new stimuli were presented again (Pair 3) and a feature in a previously unrewarded dimension was rewarded (e.g. furry external texture).
rewarded (e.g. a jasmine odor; a test of perseveration). The fifth and critical test for assessing executive function was an extradimensional shift (ED), where a new set of pots were presented (Table 2) and the reward was paired with a feature in a new sensory dimension (e.g. fur on the outside of a pot), which required a shift of attention from the previously rewarded stimulus dimension (odor) to a new dimension (external texture); (6) this was followed by a second reversal (REV2) within this new dimension (e.g. external texture; another assessment of perseveration); (7) and a learned irrelevance test (LI) where a change was made in the third sensory dimension which had never been varied or rewarded during the test (e.g. the digging medium) while keeping the reward cue the same (i.e. external texture), thus assessing rats’ ability to ignore irrelevant stimuli, an important aspect of attentional processing [19]. The sensory dimensions of ED attention shifts were balanced across rats. 2.4. Tissue processing Following testing, animals were deeply anesthetized with 4.0% isoflurane, transcardially perfused with ice-cold 0.9% heparinized
saline and 4.0% paraformaldehyde (PFA). Brains were removed and stored overnight in PFA at 4 ◦ C and then transferred to 20% sucrose in phosphate-buffered saline and stored at 4 ◦ C until saturated. Coronal slices were cut at 20 m with a cryostat, stained with cresyl violet and examined for needle placement and lesion size by an experimenter who was blinded to experimental conditions. To calculate PFC infarct volume (ImageJ 1.36b software, National Institutes of Health), sections were measured at 400 m intervals throughout the frontal lobes from bregma +5 mm AP to −1 mm AP, and the infarct volume was calculated as: (the average area of remaining damaged tissue in each section) × (number of sections analyzed) × (distance between sections) [20]. Because of the bilateral nature of damage, the contralateral hemisphere could not be used as a control, therefore the measured volume does not account for lost, shrunken or replaced tissue. Evident gliosis within the MD was taken as a measure of injury since the small injections of ET-1 created lacunar-like injury rather than frank infarcts. To calculate MD gliosis volume, sections were measured at 80 m intervals throughout the thalamus and volume was calculated as (average area of gliosis within MD) × (number of sections analyzed) × (distance between sections).
Fig. 1. Representative injury profile of animals with bilateral ischemic damage in the (A) prefrontal cortex (13.7 ± 3.7 mm3 (mean ± SEM)) and (B) evident gliosis in the mediodorsal thalamus (0.404 ± 0.063 mm3 (mean ± SEM)). Areas depicted are maximum (light gray), minimum (black) and median (dark gray) extent of ET-1 injury. Brain sections adapted from Paxinos and Watson (numbers correspond to millimeters from bregma) [39].
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Fig. 2. Mean number of trials to criterion (±SEM) on the attention set shift tests. Ischemic PFC rats required significantly more trials to criterion than sham subjects on the extradimensional (ED) shift, indicating an impairment in the ability to shift attention to a new stimulus dimension (*p < 0.05). There were no differences among ischemic groups in the performance of the interdimensional shift (ID), simple and compound discriminations (SD and CD), reversals (REV1 and REV2) and the test of learned irrelevance (LI).
2.5. Statistical analysis A series of univariate analysis of variances (ANOVA) were used to assess the effects of ischemia in MD and PFC on acquisition, reversals, attention shifts and learned irrelevance. Tukey’s honestly significant difference criterion was used for multiple comparisons. A subsequent Pearson product-moment correlation coefficient was calculated in order to assess the relationship between functional deficit and volume of ischemic damage. Statistical significance was considered at p ≤ 0.05.
p = 0.329) or the test of learned irrelevance (ED: F2,30 = 0.37, p = 0.693) (Fig. 2). 3.3. Relationship between PFC infarct and functional deficit A Pearson product-moment correlation between PFC infarct volume and ED performance did not reach statistical significance (r = 0.51, p > 0.05), although there was a positive relationship between these variables, with 26% of the variance explained by lesion volume alone (Fig. 3).
3. Results
4. Discussion
3.1. Infarct assessment
The current study investigated the effects of ischemic damage within the PFC and MD on executive cognitive function. Ischemic damage to medial prefrontal cortex resulted in a selective impairment in the ability to shift attention between stimulus dimensions, the ED shift. However, rats with PFC damage did not differ from control groups in any other measures used in the test, indicating a selective dysfunction in shifting attention set and not in
ET-1 injections in prefrontal cortex created ischemic infarcts that had an average volume of 13.7 ± 3.7 mm3 (mean ± SEM) and typically included prelimbic, infralimbic and anterior cingulate cortex (Fig. 1A). One subject was excluded for inadequate lesion size (<4 mm3 ). Mediodorsal thalamic damage was more difficult to quantify due to the relatively small amounts of ET-1 injected (0.25 L) and the length of time before sacrifice. However, in order to quantify the injury, we calculated the volume of evident MD gliosis. On average, animals displayed gliosis measuring 0.404 ± 0.063 mm3 (mean ± SEM) in each MD nucleus (Fig. 1B). Animals were included in the behavioral analyses only if bilateral damage (i.e. evident gliosis) was noted within the MD. All animals (n = 14) met this criterion. 3.2. Behavioral analysis An ANOVA of the extradimensional attention shifts revealed a significant effect of Lesion on performance (ED: F2,30 = 5.32, p = 0.011; Fig. 2). Rats with PFC damage required significantly more trials to reach criterion performance relative to sham-lesion controls on tests when attention shifted between stimulus dimensions (ED) (p < 0.05); but not when the attention shifts were maintained within a stimulus dimension (ID) (p > 0.05; Fig. 2). In contrast, MD rats did not significantly differ from sham-lesion rats on either the ED (p > 0.05) or ID (p > 0.05). Consistent with our hypothesis, PFC or MD infarcts did not affect performance acquisition (SD: F2,30 = 1.42, p = 0.258, CD: F2,30 = 0.27, p = 0.767), reversals (REV1: F2,30 = 0.03, p = 0.970, REV2: F2,30 = 1.15,
Fig. 3. Scatter plot with line of best fit demonstrating the relationship between prefrontal cortex (PFC) infarct volume (mm3 ) and functional deficit in the extradimensional (ED) shift. Although positive, the Pearson product-moment correlation failed to reach statistical significance (p > 0.05).
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acquisition, attention shifting or perseveration. Further, ischemic lesions of the MD did not impair performance in any of the measures of attention shifting compared to sham surgery. The results of the current study are the first demonstration that an impairment of executive function can arise from a rodent model of ischemic stroke within the PFC. Critically, these findings closely parallel the selective impairment of set shifting ability of humans in the WCST following stroke in the dorsolateral region of the prefrontal cortex, an area thought to be homologous to the rodent PFC [2–5,21]. Although there was a positive relationship, the fact that there was no significant correlation between PFC infarct volume and ED performance leads one to speculate that location of ischemic damage is a greater contributor to this functional deficit than overall infarct volume. In this study, bilateral lesions were used to model human impairments that commonly arise from unilateral damage in the PFC [22] or MD [9]. Because human executive cognitive function is much more lateralized than rodent brain function [23,24] robust cognitive impairments result from unilateral stroke in humans. In rodents however, bilateral injury is commonly induced [25,26] and was validated in the current study to create cognitive impairments of a similar magnitude as would occur in humans [21,27]. Our results are also similar to previous findings of set shifting impairments in rats following excitotoxic lesions of PFC [16]. Contrary to our hypothesis, damage to the MD did not produce deficits in the ED shift of the attention set shifting test. It is possible that the lesions to MD (0.404 mm3 ) were not sufficiently large enough to disrupt attentional processing in the PFC or that afferents from the MD are not necessary for attention set shifting in rodents. However, this latter hypothesis is unlikely because deficits in behavioral strategy shifting are prominent following bilateral infusions of 0.5 L bupivicaine into MD nucleus of rats [24]. Because of differences in drug mechanisms of action and outcomes, it is impossible to directly compare the current results, however, that study [24] demonstrated an integral role of the MD in rodent executive functioning. Other inactivation and lesion studies in rats further highlight the importance of the MD thalamus in higher-order cognitive functioning [28,29]. Therefore, slightly larger areas of damage in the MD may be required in order to precipitate executive dysfunction. These data should be considered in future studies of ischemia-induced executive dysfunction targeting the MD nucleus. Cognitive impairment has been proposed to arise from several types of vascular lesions including single or multiple infarcts, chronic hypoperfusion and white matter damage, also referred to as leukoaraiosis [30]. While these lesions can affect the prefrontal circuitry including the PFC and MD, they may also damage axon tracts in subcortical structures that were not investigated in the current study. For example, the volume of MRI white matter injury (i.e. hyperintensities) resulting from hypoperfusion is higher in the prefrontal region than in other cortical regions [31]. Patients with both lacunar infarcts and cognitive decline have more white matter lesions in the frontal lobes whose severity correlates with executive dysfunction [32,33]. Further, patients with multiple cerebral infarcts have lower perfusion rates and metabolic activity in frontal cortex [34] correlating with reduced executive function [35]. These types of insults are important contributors to cognitive dysfunction in humans, but are difficult to model preclinically. Nonetheless, the data obtained in the current study, represent the first steps in developing an animal model of ischemia-induced executive dysfunction. Cognitive impairments are often overlooked in preclinical studies [36], but can be very devastating to patients and families [37]. Further development of animal models to assess interventional therapies for ‘frontal-syndrome’ deficits will be an instrumental step in counteracting stroke associated executive dysfunction.
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