Anterior Thalamic Nuclei Lesions Research Articles

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory in rats.

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of biconditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-s trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory.

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology.SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.

Environmental enrichment increases prefrontal EEG power and synchrony with the hippocampus in rats with anterior thalamus lesions.

The anterior thalamic nuclei (ATN) are a major interface between the hippocampus and prefrontal cortex within an extended Papez circuit. Rat models suggest that the deficits caused by ATN damage, which is associated with "diencephalic amnesia", can be ameliorated by environmental enrichment (EE) through unknown mechanisms. We examined whether changes in theta rhythmicity within and between the hippocampus and prefrontal cortex are influenced by EE in rats with ATN lesions. Here, we show that ATN lesions and EE produced essentially opposed functional effects in terms of changes in rhythmicity between two consecutive trials when rats forage for chocolate hail. On the second trial, standard-housed rats with ATN lesions showed: (a) a clear reduction in prefrontal cortex experience-dependent power change in the theta band and in two adjacent bands; (b) little change in the theta band in hippocampal area CA1; and (c) only a modest overall reduction in experience-dependent power change at lower theta frequencies in the dentate gyrus. EE exposure prevented the decrease in prefrontal theta power in rats with ATN lesions, and in fact caused a clear increase in prefrontal cortex power across all bands. While ATN lesions did not reliably affect prefrontal-CA1 or prefrontal-dentate theta coherence, EE increased the coherence between prefrontal cortex and area CA1 in both the sham and ATN groups. Thus, EE increases functional connectivity between prefrontal cortex and hippocampus via pathways that bypass the ATN, and increases behaviorally dependent prefrontal rhythmicity. These EEG effects may contribute to improved learning and memory in the ATN-lesion model of diencephalic amnesia.

Do the rat anterior thalamic nuclei contribute to behavioural flexibility?

The rodent anterior thalamic nuclei (ATN) are vital for spatial memory. A consideration of their extensive frontal connections suggests that these nuclei may also subserve non-spatial functions. The current experiments explored the importance of the ATN for different aspects of behavioural flexibility, including their contribution to tasks typically associated with frontal cortex. In Experiment 1, rats with ATN lesions were tested on a series of response and visual discriminations in an operant box and, subsequently, in a water tank. The tasks included assessments of reversal learning as well switches between each discrimination dimension. Results revealed a mild and transient deficit on the operant task that was not specific to any stage of the procedure. In the water tank, the lesion animals were impaired on the reversal of a spatial discrimination but did not differ from controls on any other measure. Experiment 2 examined the impact of ATN damage on a rodent analogue of the ‘Stroop’, which assesses response choice during stimulus conflict. The lesion animals successfully acquired this task and were able to use contextual information to disambiguate conflicting cue information. However, responding during the initial presentation of conflicting cue information was affected by the lesion. Taken together, these results suggest that the ATN are not required for aspects of behavioural flexibility (discrimination learning, reversals or high-order switches) typically associated with the rat medial prefrontal cortex. The results from Experiment 2 suggest that the non-spatial functions of the ATN may be more aligned with those of the anterior cingulate cortex.

Anterior thalamic nuclei, but not retrosplenial cortex, lesions abolish latent inhibition in rats.

The present study examined the effects of excitotoxic lesions in 2 closely related structures, the anterior thalamic nuclei and the retrosplenial cortex, on latent inhibition. Latent inhibition occurs when nonreinforced preexposure to a stimulus retards the subsequent acquisition of conditioned responding to that stimulus. Latent inhibition was assessed in a within-subject procedure with auditory stimuli and food reinforcement. As expected, sham-operated animals were slower to acquire conditioned responding to a stimulus that had previously been experienced without consequence, relative to a non-preexposed stimulus. This latent inhibition effect was absent in rats with excitotoxic lesions in the anterior thalamic nuclei, as these animals conditioned to both stimuli at equivalent rates. The retrosplenial lesions appeared to spare latent inhibition, as these animals displayed a robust stimulus preexposure effect. The demonstration here that anterior thalamic nuclei lesions abolish latent inhibition is consistent with emerging evidence of the importance of these thalamic nuclei for attentional control.

Anterior thalamic nuclei lesions have a greater impact than mammillothalamic tract lesions on the extended hippocampal system.

The anterior thalamic nuclei (ATN), mammillary bodies and their interconnecting fiber tract, the mammillothalamic tract (MTT), are important components of an extended hippocampal circuit for episodic memory. In humans, damage to the MTT or ATN in many disorders is associated with severe anterograde amnesia and it is assumed that their influence on memory is functionally equivalent. The relative influence of these two structures on memory has not, however, been assessed explicitly. Here, a direct comparison found that only ATN lesions impaired spatial reference memory in rats. ATN lesions produced more severe deficits on spatial working memory and reduced zif268 expression to a greater degree and in more corticolimbic sites than did MTT lesions. Conversely, MTT lesions reduced NeuN cell counts in all three subregions of the MB to a greater extent than did ATN lesions, so their relative impact cannot be explained by retrograde neuropathology of the MB. Hence ATN injury causes a more critical dysfunction than would be expected by an emphasis on the indirect influence of brainstem inputs to the extended memory system. The greater ATN lesion deficits found here may represent the consequence of disruption to the direct connections of the ATN with both hippocampal and cortical sites.

Post-training Inactivation of the Anterior Thalamic Nuclei Impairs Spatial Performance on the Radial Arm Maze.

The limbic thalamus, specifically the anterior thalamic nuclei (ATN), contains brain signals including that of head direction cells, which fire as a function of an animal's directional orientation in an environment. Recent work has suggested that this directional orientation information stemming from the ATN contributes to the generation of hippocampal and parahippocampal spatial representations, and may contribute to the establishment of unique spatial representations in radially oriented tasks such as the radial arm maze. While previous studies have shown that ATN lesions can impair spatial working memory performance in the radial maze, little work has been done to investigate spatial reference memory in a discrimination task variant. Further, while previous studies have shown that ATN lesions can impair performance in the radial maze, these studies produced the ATN lesions prior to training. It is therefore unclear whether the ATN lesions disrupted acquisition or retention of radial maze performance. Here, we tested the role of ATN signaling in a previously learned spatial discrimination task on a radial arm maze. Rats were first trained to asymptotic levels in a task in which two maze arms were consistently baited across training. After 24 h, animals received muscimol inactivation of the ATN before a 4 trial probe test. We report impairments in post-inactivation trials, suggesting that signals from the ATN modulate the use of a previously acquired spatial discrimination in the radial-arm maze. The results are discussed in relation to the thalamo-cortical limbic circuits involved in spatial information processing, with an emphasis on the head direction signal.

Impaired spatial working memory after anterior thalamic lesions: recovery with cerebrolysin and enrichment.

Lesions to the anterior thalamic nuclei (ATN) in rats produce robust spatial memory deficits that reflect their influence as part of an extended hippocampal system. Recovery of spatial working memory after ATN lesions was examined using a 30-day administration of the neurotrophin cerebrolysin and/or an enriched housing environment. As expected, ATN lesions in standard-housed rats given saline produced severely impaired reinforced spatial alternation when compared to standard-housed rats with sham lesions. Both cerebrolysin and enrichment substantially improved this working memory deficit, including accuracy on trials that required attention to distal cues for successful performance. The combination of cerebrolysin and enrichment was more effective than either treatment alone when the delay between successive runs in a trial was increased to 40s. Compared to the intact rats, ATN lesions in standard-housed groups produced substantial reduction in c-Fos expression in the retrosplenial cortex, which remained low after cerebrolysin and enrichment treatments. Evidence that multiple treatment strategies restore some memory functions in the current lesion model reinforces the prospect for treatments in human diencephalic amnesia.

The impact of fornix lesions in rats on spatial learning tasks sensitive to anterior thalamic and hippocampal damage

The present study sought to understand how the hippocampus and anterior thalamic nuclei are conjointly required for spatial learning by examining the impact of cutting a major tract (the fornix) that interconnects these two sites. The initial experiments examined the consequences of fornix lesions in rats on spatial biconditional discrimination learning. The rationale arose from previous findings showing that fornix lesions spare the learning of spatial biconditional tasks, despite the same task being highly sensitive to both hippocampal and anterior thalamic nuclei lesions. In the present study, fornix lesions only delayed acquisition of the spatial biconditional task, pointing to additional contributions from non-fornical routes linking the hippocampus with the anterior thalamic nuclei. The same fornix lesions spared the learning of an analogous nonspatial biconditional task that used local contextual cues. Subsequent tests, including T-maze place alternation, place learning in a cross-maze, and a go/no-go place discrimination, highlighted the impact of fornix lesions when distal spatial information is used flexibly to guide behaviour. The final experiment examined the ability to learn incidentally the spatial features of a square water-maze that had differently patterned walls. Fornix lesions disrupted performance but did not stop the rats from distinguishing the various corners of the maze. Overall, the results indicate that interconnections between the hippocampus and anterior thalamus, via the fornix, help to resolve problems with flexible spatial and temporal cues, but the results also signal the importance of additional, non-fornical contributions to hippocampal-anterior thalamic spatial processing, particularly for problems with more stable spatial solutions.

Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex, but enrichment rescues CA1 spines only.

Injury to the anterior thalamic nuclei (ATN) may affect both hippocampus and retrosplenial cortex thus explaining some parallels between diencephalic and medial temporal lobe amnesias. We found that standard-housed rats with ATN lesions, compared with standard-housed controls, showed reduced spine density in hippocampal CA1 neurons (basal dendrites, -11.2%; apical dendrites, -9.6%) and in retrospenial granular b cortex (Rgb) neurons (apical dendrites, -20.1%) together with spatial memory deficits on cross maze and radial-arm maze tasks. Additional rats with ATN lesions were also shown to display a severe deficit on spatial working memory in the cross-maze, but subsequent enriched housing ameliorated their performance on both this task and the radial-arm maze. These enriched rats with ATN lesions also showed recovery of both basal and apical CA1 spine density to levels comparable to that of the standard-housed controls, but no recovery of Rgb spine density. Inspection of spine types in the CA1 neurons showed that ATN lesions reduced the density of thin spines and mushroom spines, but not stubby spines; while enrichment promoted recovery of thin spines. Comparison with enriched rats that received pseudo-training, which provided comparable task-related experience, but no explicit spatial memory training, suggested that basal CA1 spine density in particular was associated with spatial learning and memory performance. Distal pathology in terms of reduced integrity of hippocampal and retrosplenial microstructure provides clear support for the influence of the ATN lesions on the extended hippocampal system. The reversal by postoperative enrichment of this deficit in the hippocampus but not the retrosplenial cortex may indicate region-specific mechanisms of recovery after ATN injury.

Selective importance of the rat anterior thalamic nuclei for configural learning involving distal spatial cues

To test potential parallels between hippocampal and anterior thalamic function, rats with anterior thalamic lesions were trained on a series of biconditional learning tasks. The anterior thalamic lesions did not disrupt learning two biconditional associations in operant chambers where a specific auditory stimulus (tone or click) had a differential outcome depending on whether it was paired with a particular visual context (spot or checkered wall-paper) or a particular thermal context (warm or cool). Likewise, rats with anterior thalamic lesions successfully learnt a biconditional task when they were reinforced for digging in one of two distinct cups (containing either beads or shredded paper), depending on the particular appearance of the local context on which the cup was placed (one of two textured floors). In contrast, the same rats were severely impaired at learning the biconditional rule to select a specific cup when in a particular location within the test room. Place learning was then tested with a series of go/no-go discriminations. Rats with anterior thalamic nuclei lesions could learn to discriminate between two locations when they were approached from a constant direction. They could not, however, use this acquired location information to solve a subsequent spatial biconditional task where those same places dictated the correct choice of digging cup. Anterior thalamic lesions produced a selective, but severe, biconditional learning deficit when the task incorporated distal spatial cues. This deficit mirrors that seen in rats with hippocampal lesions, so extending potential interdependencies between the two sites.

A role for anterior thalamic nuclei in contextual fear memory

Understanding the neural processes that govern the attribution of a predictive value to environmental stimuli is a major issue in behavioural neuroscience. The main strategy to explore this question has been the use of Pavlovian fear conditioning paradigms. While a majority of studies have focussed on the specific role of the hippocampus and amygdala in contextual versus cued fear, very few studies examined the potential role of subcortical limbic areas. Among those, the anterior thalamic nuclei (ATN) connect to both the hippocampus and the amygdala and also to the cingulate region which is known to support fear-related activity. Here, we show that rats sustaining ATN lesions exhibit a specific impairment following context but not tone conditioning. ATN lesions slowed down acquisition without preventing normal freezing behaviour when rats were reexposed to the conditioning context 24h later. However, ATN rats exhibited poor retrieval of contextual but not cued fear when assessed 3weeks after conditioning. In addition, extinction was faster in ATN rats and spontaneous recovery of contextual fear was impaired by the lesions. These deficits indicate that contextual fear memories established in the absence of the ATN are not robust. Collectively, these findings support an involvement of the ATN in the circuits underlying contextual fear memory.

Dissociation of recognition and recency memory judgments after anterior thalamic nuclei lesions in rats.

The anterior thalamic nuclei form part of a network for episodic memory in humans. The importance of these nuclei for recognition and recency judgments remains, however, unclear. Rats with anterior thalamic nuclei lesions and their controls were tested on object recognition, along with two types of recency judgment. The spontaneous discrimination of a novel object or a novel odor from a familiar counterpart (recognition memory) was not affected by anterior thalamic lesions when tested after retention delays of 1 and 60 min. To measure recency memory, rats were shown two familiar objects, one of which had been explored more recently. In one condition, rats were presented with two lists (List A, List B) of objects separated by a delay, thereby creating two distinct blocks of stimuli. After an additional delay, rats were presented with pairs of objects, one from List A and one from List B (between-block recency). No lesion-induced deficit was apparent for recency discriminations between objects from different lists, despite using three different levels of task difficulty. In contrast, rats with anterior thalamic lesions were significantly impaired when presented with a continuous list of objects and then tested on their ability to distinguish between those items early and late in the same list (within-block recency). The contrasting effects on recognition and recency support the notion that interlinked hippocampal–anterior thalamic interconnections support aspects of both spatial and nonspatial learning, although the role of the anterior thalamic nuclei may be restricted to a subclass of recency judgments (within-block).

Reduced cytochrome oxidase activity in the retrosplenial cortex after lesions to the anterior thalamic nuclei

The anterior thalamic nuclei (ATN) make a critical contribution to hippocampal system functions. Growing experimental work shows that the effects of ATN lesions often resemble those of hippocampal lesions and both markedly reduce the expression of immediate-early gene markers in the retrosplenial cortex, which still appears normal by standard histological means. This study shows that moderate ATN damage was sufficient to produce severe spatial memory impairment as measured in a radial-arm maze. Furthermore, ATN rats exhibited reduced cytochrome oxidase activity in the most superficial cortical layers of the granular retrosplenial cortex, and, to a lesser extent, in the anterior cingulate cortex. By contrast, no change in cytochrome oxidase activity was observed in other limbic cortical regions or in the hippocampal formation. Altogether our results indicate that endogenous long-term brain metabolic capacity within the granular retrosplenial cortex is compromised by even limited ATN damage.

A role for anterior thalamic nuclei in affective cognition: Interaction with environmental conditions

Damage to anterior thalamic nuclei (ATN) is a well-known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard-housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c-Fos and phosphorylated cAMP response element-binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c-Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard-housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions.

The role of the anterior, mediodorsal, and parafascicular thalamus in instrumental conditioning

The traditional animal model of instrumental behavior has focused almost exclusively on structures within the cortico-striatal network and ignored the contributions of various thalamic nuclei despite large and specific connections with each of these structures. One possible reason for this is that the thalamus has been conventionally viewed as a mediator of general processes, such as attention, arousal and movement, that are not easily separated from more cognitive aspects of instrumental behavior. Recent research has, however, begun to separate these roles. Here we review the role of three thalamic nuclei in instrumental conditioning: the anterior thalamic nuclei (ANT), the mediodorsal (MD), and parafascicular thalamic nuclei (PF). Early research suggested that ANT might regulate aspects of instrumental behavior but, on review, we suggest that the types of tasks used in these studies were more likely to recruit Pavlovian processes. Indeed lesions of ANT have been found to have no effect on performance in instrumental free-operant tasks. By contrast the mediodorsal thalamus (MD) has been found to play a specific and important role in the acquisition of goal-directed action. We propose this role is related to its connections with prelimbic cortex (PL) and present new data that directly implicates this circuit in the acquisition of goal-directed actions. Finally we review evidence suggesting the PF, although not critical for the acquisition or performance of instrumental actions, plays a specific role in regulating action flexibility.

Anterior thalamic nuclei lesions in rats disrupt markers of neural plasticity in distal limbic brain regions

In two related experiments, neurotoxic lesions were placed in the anterior thalamic nuclei of adult rats. The rats were then trained on behavioral tasks, immediately followed by the immunohistochemical measurement of molecules linked to neural plasticity. These measurements were made in limbic sites including the retrosplenial cortex, the hippocampal formation, and parahippocampal areas. In Experiment 1, rats with unilateral anterior thalamic lesions explored either novel or familiar objects prior to analysis of the immediate-early gene zif268. The lesions reduced zif268 activity in the granular retrosplenial cortex and postsubiculum. Exploring novel objects resulted in local changes of hippocampal zif268, but this change was not moderated by anterior thalamic lesions. In Experiment 2, rats that had received either bilateral anterior thalamic lesions or control surgeries were exposed to novel room cues while running in the arms of a radial maze. In addition to zif268, measurements of c-AMP response element binding protein (CREB), phosphorylated CREB (pCREB), and growth associated protein43 (GAP-43) were made. As before, anterior thalamic lesions reduced zif268 in retrosplenial cortex and postsubiculum, but there were also reductions of pCREB in granular retrosplenial cortex. Again, the hippocampus did not show lesion-induced changes in zif268, but there were differential effects on CREB and pCREB consistent with reduced levels of hippocampal CREB phosphorylation following anterior thalamic damage. No changes in GAP-43 were detected. The results not only point to changes in several limbic sites (retrosplenial cortex and hippocampus) following anterior thalamic damage, but also indicate that these changes include decreased levels of pCREB. As pCREB is required for neuronal plasticity, partly because of its regulation of immediate early-gene expression, the present findings reinforce the concept of an ‘extended hippocampal system’ in which hippocampal function is dependent on distal sites such as the anterior thalamic nuclei.

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with sham-operated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory.

Anterior thalamic lesions alter both hippocampal-dependent behavior and hippocampal acetylcholine release in the rat

The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo measures of ACh are correlated to learning and memory performance. In the present study, complete lesions of the ATN impaired performance on two measures of hippocampal-dependent learning and memory (spontaneous alternation and delayed alternation) and severely disrupted behaviorally evoked ACh efflux within the hippocampus of adult male rats. In contrast, incomplete ATN lesions did not impair spontaneous alternation performance but did impair delayed alternation performance while blunting hippocampal ACh efflux. Interestingly, ATN lesions of any size did not affect basal concentrations of ACh in the hippocampus. These results demonstrate that the ATN have the capacity to modulate behaviorally relevant neuronal transmission within the hippocampus.

Post-surgical interval and lesion location within the limbic thalamus determine extent of retrosplenial cortex immediate-early gene hypoactivity

Four experiments examined the disruptive effects of selective lesions in limbic thalamic nuclei on retrosplenial cortex function, as characterized by striking changes in immediate-early gene activity. Major goals were to test the specificity of these retrosplenial changes, to define better their time course, and to assess the spread of retrosplenial dysfunction with time post-surgery. Experiment 1 examined the activity of two immediate-early genes (c-Fos, Zif268) in the retrosplenial cortex after unilateral anterior thalamic nuclei lesions (1, 2, or 8 weeks post-surgery). Marked immediate-early gene hypoactivity in the hemisphere ipsilateral to the thalamic lesion was consistent across these different post-surgical intervals and, hence, across different rat strains. Concurrent processing of brain tissues from rats either 4 weeks or 1 year after anterior thalamic lesions (Experiments 2 and 3) enabled direct comparisons across very different survival times. The results confirmed that over time the immediate-early gene disruption expanded from the superficial laminae to the deep laminae of granular b cortex and to the dysgranular subregion, indicative of more global disruptions to retrosplenial cortex with extended survival. Associated, subtle changes to cell morphometry (size and sphericity) were found in the retrosplenial cortex. In contrast, unilateral lesions in the adjacent laterodorsal thalamic nucleus (Experiment 4) did not significantly alter retrosplenial cortex c-Fos activity, so highlighting the anatomical specificity of the anterior thalamic lesion effects. These findings not only indicate that the impact of anterior thalamic lesions on cognition could be enhanced by retrosplenial cortex dysfunction but they also show that the effects could increase with longer post-insult survival.