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.

A critical role for the anterior thalamus in directing attention to task-relevant stimuli.

The prefrontal cortex mediates adaption to changing environmental contingencies. The anterior thalamic nuclei, which are closely interconnected with the prefrontal cortex, are important for rodent spatial memory, but their potential role in executive function has received scant attention. The current study examined whether the anterior thalamic nuclei are involved in attentional processes akin to those of prefrontal regions. Remarkably, the results repeatedly revealed attentional properties opposite to those of the prefrontal cortex. Two separate cohorts of rats with anterior thalamic lesions were tested on an attentional set-shifting paradigm that measures not only the ability of stimuli dimensions that reliably predict reinforcement to gain attention ("intradimensional shift"), but also their ability to shift attention to another stimulus dimension when contingencies change ("extradimensional shift"). In stark contrast to the effects of prefrontal damage, anterior thalamic lesions impaired intradimensional shifts but facilitated extradimensional shifts. Anterior thalamic lesion animals were slower to acquire discriminations based on the currently relevant stimulus dimension but acquired discriminations involving previously irrelevant stimulus dimensions more rapidly than controls. Subsequent tests revealed that the critical determinant of whether anterior thalamic lesions facilitate extradimensional shifts is the degree to which the stimulus dimension has been established as an unreliable predictor of reinforcement over preceding trials. This pattern of performance reveals that the anterior thalamic nuclei are vital for attending to those stimuli that are the best predictors of reward. In their absence, unreliable predictors of reward usurp attentional control.

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.

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.

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.

The extended hippocampal-diencephalic memory system: enriched housing promotes recovery of the flexible use of spatial representations after anterior thalamic lesions.

The anterior thalamic (AT) nuclei constitute an important component of an extended hippocampal-diencephalic system, and severe persisting memory deficits are normally found after AT damage. This study examined whether postoperative enrichment promotes the recovery of the flexible use of spatial representations in rats with AT lesions. After training to swim from a single constant start position to a submerged platform in a Morris water maze, rats with AT lesions that were housed in standard cages (AT-Std) performed poorly when required to swim to the platform from novel start positions during probe trials. By contrast, rats with AT lesions but housed in enriched environments (AT-Enr), like sham-lesion rats, showed relatively little disruption when tested with novel start positions. AT-Std rats also initially showed impaired acquisition of the task, whereas AT-Enr rats learned at a similar rate to that of the Sham-Std group. Beneficial effects of enrichment were replicated in the subsequent standard water maze procedure that used varying start positions throughout training to acquire a new platform location. Although it is clear that AT damage can severely disrupt episodic-like memory processes, and appear to be a core part of the interlinked neural systems subserving episodic memory, the current findings strongly encourage study on the adaptive response of the brain to thalamic lesions and prospects for the development of rehabilitation programs in cases of anterograde amnesia associated with diencephalic injury.

Behavioral and hypothalamic-pituitary-adrenal responses to anterodorsal thalami nuclei lesions and variable chronic stress in maternally separated rats.

In maternally separated rats, variable chronic stress decreased the emotional reactivity and provoked a state of hypoactivity of the hypothalamic-pituitary-adrenal system at 3 months old but increased its activity after the open field test. The anterodorsal thalami nuclei control of the endocrine response under stress conditions was not manifested however its seems activate grooming behavior. The development of behavioral and endocrine response to stress is influenced by early postnatal environment. On the other hand, the anterodorsal thalami nuclei exert an inhibitory influence on the hypothalamic-pituitary-adrenal system under basal and stressful conditions. The aim of this work is to determine the magnitude of behavioral and hypothalamic-pituitary-adrenal responses to variable chronic stress in adult female rats with anterodorsal thalami nuclei lesions, previously isolated for 4.5 h daily during the first 3 weeks of life. The groups were: non-maternally separated sham and lesioned, maternally separated sham and lesioned with variable chronic stress with and without open field test. At 3 months old, under variable chronic stress, maternal separation provoked an increase in ambulation in sham and lesioned animals (P<0.01) but this parameter was not modified by lesion in either non-maternally separated or maternally separated groups. Neither the lesion nor the maternal separation changed the defecation and rearing parameter. Grooming behavior was lower in maternally separated lesioned rats (P<0.05). Under variable chronic stress maternal separation decreased adrenocorticotrophin hormone in comparison with non-maternally separated (P<0.001) and the lesion did not alter this response. Regarding corticosterone concentrations, maternal separation did not affect this hormone under variable chronic stress conditions and after the open field test there was an increase of this in both non-maternally separated and maternally separated sham and lesioned (P<0.001).

Spatial conditional associative learning: effects of thalamo-hippocampal disconnection in rats.

Unilateral lesions to the anterior thalamic nuclei (ATN) and the hippocampus (H) were made in opposite hemispheres in the rat to examine whether these brain structures form part of a functional neural pathway underlying spatial learning and memory. In the first experiment, rats were tested on a spatial-visual conditional associative task in which they had to learn to approach one of two stimuli depending on the spatial context in which the stimuli were embedded. The rats were subsequently trained on delayed forced alternation, a spatial working memory task known to be sensitive to the effects of ATNxH damage. Rats with ATNxH lesions were impaired in the acquisition of both tasks in comparison with normal control animals. The findings support the idea that the anterior thalamic nuclei and the hippocampus are critical components of an anatomical system subserving spatial memory and suggest that these brain regions work in a dependent fashion during the performance of certain spatial learning tasks.

Periodic maternal deprivation and lesion of anterodorsal thalami nuclei induce alteration on hypophyso adrenal system activity in adult rats.

The hypothalamic-pituitary-adrenal (HPA) axis is normally regulated by extrahypothalamic limbic structures, among these, the anterodorsal thalami nuclei (ADTN), which exert an inhibitory influence on HPA, in basal and acute stress conditions in rats. In the present work we have investigated whether neonatal maternal deprivation (MD) produces long-term changes in the ADTN regulation of HPA activity. Maternal deprivation, in female rats, for 4.5 hs daily, during the first 3 weeks of life, produced at 3 months old, a significant decrease in plasma ACTH concentration (p<0.001) and an increase in plasma corticosterone (C) (p<0.001), compared to control non-deprived rats (NMD). Also MD showed higher plasma epinephrine (E) and norepinephrine (NE) levels than NMD rats. The increase of NE (66.6% p<0.001) was higher than that observed in E (19%). After 30 days of ADTN lesion, plasma ACTH values were higher than in sham lesioned rats, in both NMD and MD animals. ACTH response was greater in MD rats. Plasma C, in NMD, was higher, whereas in MD lesioned animals, it was significantly lower than in sham lesioned. In MD rats, lesion produced a significant increase in plasma E and NE (p<0.001), and again, NE increase was higher than E increase. The more accentuated increase of NE than E, suggests sympathetic nervous system hyperactivity. In summary, neonatal maternal deprivation induces long-term alterations on HPA axis sensitivity and medullo adrenal secretion; enhanced sympathetic nervous system activity and, therefore affected the ADTN inhibitory influence on ACTH and adrenal glands secretion.

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 24 h later. However, ATN rats exhibited poor retrieval of contextual but not cued fear when assessed 3 weeks 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.

Effects of thalamic lesions on repeated relearning of a spatial working memory task.

Anterior thalamic (ATN) dysfunction produces memory deficits in rats and humans. The current study shows that, with a substantial delay between post-surgery tests, controls show repeated relearning on a spatial working memory task whereas rats with neurotoxic ATN lesions showed repeated relearning deficits. Rats were pre-trained to criterion, but not over trained, on the spatial task. ATN lesions produced the expected spatial memory and relearning deficits about two weeks post-surgery and again either one or 15 weeks later. Control rats also showed forgetting post-surgery and after a 15 week break, relearning the task on each occasion. Controls with only a 1 week break before their final re-test showed negligible forgetting. Thus, a short break between re-tests replicated previous findings with ATN lesions, but a long break allows repeated comparison of rates of learning from a common starting point in sham and ATN-lesioned animals, providing a useful paradigm for future testing of pro-cognitive treatments.

Thalamic control of human attention driven by memory and learning.

The role of the thalamus in high-level cognition-attention, working memory (WM), rule-based learning, and decision making-remains poorly understood, especially in comparison to that of cortical frontoparietal networks [1-3]. Studies of visual thalamus have revealed important roles for pulvinar and lateral geniculate nucleus in visuospatial perception and attention [4-10] and for mediodorsal thalamus in oculomotor control [11]. Ventrolateral thalamus contains subdivisions devoted to action control as part of a circuit involving the basal ganglia [12, 13] and motor, premotor, and prefrontal cortices [14], whereas anterior thalamus forms a memory network in connection with the hippocampus [15]. This connectivity profile suggests that ventrolateral and anterior thalamus may represent a nexus between mnemonic and control functions, such as action or attentional selection. Here, we characterize the role of thalamus in the interplay between memory and visual attention. We show that ventrolateral lesions impair the influence of WM representations on attentional deployment. A subsequent fMRI study in healthy volunteers demonstrates involvement of ventrolateral and, notably, anterior thalamus in biasing attention through WM contents. To further characterize the memory types used by the thalamus to bias attention, we performed a second fMRI study that involved learning of stimulus-stimulus associations and their retrieval from long-term memory to optimize attention in search. Responses in ventrolateral and anterior thalamic nuclei tracked learning of the predictiveness of these abstract associations and their use in directing attention. These findings demonstrate a key role for human thalamus in higher-level cognition, notably, in mnemonic biasing of attention.

The effects of lesions to the postsubiculum or the anterior dorsal nucleus of the thalamus on spatial learning in rats.

To investigate the role of the head direction (HD) cell circuit in spatial navigation, rats with bilateral, neurotoxic lesions to the postsubiculum (PoS; Experiment 1) or the anterior dorsal nucleus of the thalamus (ADN; Experiment 2) were compared to sham controls on 2 tasks that could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from 2 locations in the experimental room. ADN lesioned rats were impaired relative to sham controls on the first block of 8 trials, but not on the total trials taken to reach criterion. This transient deficit was not observed in rats with lesions to the PoS. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table, and return to the home cage. Both PoS and ADN lesioned rats showed impairments on this task relative to sham rats, making more errors on the return component of the foraging trip. The spatial deficits produced by lesions to the PoS and the ADN, downstream structures in the HD cell circuit, are not as severe as those observed in earlier studies in rats with lesions to the dorsal tegmental nucleus.

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.

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).

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 21 h, 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 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 in the anterior thalamic nuclei of rats do not disrupt acquisition of stimulus sequence learning.

Sequence learning and spatial alternation were examined in rats with anterior thalamic lesions or sham surgeries. There was a lesion-induced deficit in spatial alternation but not in sequence learning. During sequence learning, rats discriminated between six different sequentially presented compounds (e.g., reinforce A before B, but not B before A), composed of audio-visual elements. The solution required rats to learn both specific stimulus sequences and the reward contingencies associated with these specific temporal relationships. The failure of anterior thalamic lesions to affect the acquisition of this sequential configural task complements the recent finding that anterior thalamic lesions also spare the acquisition of a configural task involving specific stimulus pairings and their spatial relationships. These findings suggest that such "structural" learning is more reliant on cortico-hippocampal than thalamo-hippocampal interactions.