Adaptive Responding to Stimulus-Outcome Associations Requires Noradrenergic Transmission in the Medial Prefrontal Cortex.

A dynamic environment, such as the one we inhabit, requires organisms to continuously update their knowledge of the setting. While the prefrontal cortex is recognized for its pivotal role in regulating such adaptive behavior, the specific contribution of each prefrontal area remains elusive. In the current work, we investigated the direct involvement of two major prefrontal subregions, the medial prefrontal cortex (mPFC, A32D + A32V) and the orbitofrontal cortex (OFC, VO + LO), in updating pavlovian stimulus-outcome (S-O) associations following contingency degradation in male rats.

The mediodorsal thalamus in executive control.

Executive control, the ability to organize thoughts and action plans in real time, is a defining feature of higher cognition. Classical theories have emphasized cortical contributions to this process, but recent studies have reinvigorated interest in the role of the thalamus. Although it is well established that local thalamic damage diminishes cognitive capacity, such observations have been difficult to inform functional models.

Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions.

In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision-making. Such goal-directed behaviour relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents.

The mediodorsal thalamus supports adaptive responding based on stimulus-outcome associations.

The ability to engage into flexible behaviors is crucial in dynamic environments. We recently showed that in addition to the well described role of the orbitofrontal cortex (OFC), its thalamic input from the submedius thalamic nucleus (Sub) also contributes to adaptive responding during Pavlovian degradation. In the present study, we examined the role of the mediodorsal thalamus (MD) which is the other main thalamic input to the OFC.

The reuniens and rhomboid nuclei are necessary for contextual fear memory persistence in rats.

Memory persistence refers to the process by which a temporary, labile memory is transformed into a stable and long-lasting state. This process involves a reorganization of brain networks at systems level, which requires functional interactions between the hippocampus (HP) and medial prefrontal cortex (mPFC). The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are bidirectionally connected with both regions, and we previously demonstrated their crucial role in spatial memory persistence.

Targeting Reciprocally Connected Brain Regions Through CAV-2 Mediated Interventions.

An important issue in contemporary neuroscience is to identify functional principles at play within neural circuits. The reciprocity of the connections between two distinct brain areas appears as an intriguing feature of some of these circuits. This organization has been viewed as "re-entry," a process whereby two or more brain regions concurrently stimulate and are stimulated by each other, thus supporting the synchronization of neural firing required for rapid neural integration.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. All of these effects are normalised by vitamin A supplementation.

A thalamocortical circuit for updating action-outcome associations.

The ability to flexibly use knowledge is one cardinal feature of goal-directed behaviors. We recently showed that thalamocortical and corticothalamic pathways connecting the medial prefrontal cortex and the mediodorsal thalamus (MD) contribute to adaptive decision-making (Alcaraz et al., 2018).

The Cognitive Thalamus as a Gateway to Mental Representations.

Historically, the thalamus has been viewed as little more than a relay, simply transferring information to key players of the cast, the cortex and hippocampus, without providing any unique functional contribution. In recent years, evidence from multiple laboratories researching different thalamic nuclei has contradicted this idea of the thalamus as a passive structure. Dated models of thalamic functions are being pushed aside, revealing a greater and far more complex contribution of the thalamus for cognition.

Thalamocortical and corticothalamic pathways differentially contribute to goal-directed behaviors in the rat.

Highly distributed neural circuits are thought to support adaptive decision-making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat.

Insular and Ventrolateral Orbitofrontal Cortices Differentially Contribute to Goal-Directed Behavior in Rodents.

The medial prefrontal cortex (mPFC) has long been considered a critical site in action control. However, recent evidence indicates that the contribution of cortical areas to goal-directed behavior likely extends beyond mPFC. Here, we examine the function of both insular (IC) and ventrolateral orbitofrontal (vlOFC) cortices in action-dependent learning.

Parallel inputs from the mediodorsal thalamus to the prefrontal cortex in the rat.

There is a growing interest in determining the functional contribution of thalamic inputs to cortical functions. In the context of adaptive behaviours, identifying the precise role of the mediodorsal thalamus (MD) in particular remains difficult despite the large amount of experimental data available. A better understanding of the thalamocortical connectivity of this region may help to capture its functional role.

Flexible Use of Predictive Cues beyond the Orbitofrontal Cortex: Role of the Submedius Thalamic Nucleus.

The orbitofrontal cortex (OFC) is known to play a crucial role in learning the consequences of specific events. However, the contribution of OFC thalamic inputs to these processes is largely unknown. Using a tract-tracing approach, we first demonstrated that the submedius nucleus (Sub) shares extensive reciprocal connections with the OFC.

Mediodorsal but not anterior thalamic nuclei lesions impair acquisition of a conditional discrimination task.

The limbic thalamus is a heterogeneous structure with distinctive cortical connectivity. A recent review suggests that the mediodorsal thalamic nucleus (MD), unlike the anterior thalamic nuclei (ATN), may be involved in selecting relevant information in tasks relying on executive functions. We compared the effects of excitotoxic lesions of the MD or the ATN on the acquisition of a simple conditional discrimination in rats.

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.

Anterior thalamic nuclei lesions and recovery of function: Relevance to cognitive thalamus.

Injury to the anterior thalamic nuclei (ATN) and their neural connections is the most consistent neuropathology associated with diencephalic amnesia. ATN lesions in rats produce memory impairments that support a key role for this region within an extended hippocampal system of complex overlapping neural connections. Environmental enrichment is a therapeutic tool that produces substantial, although incomplete, recovery of memory function after ATN lesions, even after the lesion-induced deficit has become established.

Functional heterogeneity of the limbic thalamus: From hippocampal to cortical functions.

Today, the idea that the integrity of the limbic thalamus is necessary for normal memory functions is well established. However, if the study of thalamic patients emphasized the anterior and the mediodorsal thalamus as the critical thalamic loci supporting cognitive functions, clinical studies have so far failed to attribute a specific role to each of these regions. In view of these difficulties, we review here the experimental data conducted in rodents harboring specific lesions of each thalamic region.

Dissociable effects of anterior and mediodorsal thalamic lesions on spatial goal-directed behavior.

Goal-directed behaviors are thought to be supported by a neural circuit encompassing the prefrontal cortex, the dorsomedial striatum, the amygdala, and, as more recently suggested, the limbic thalamus. Since evidence indicates that the various thalamic nuclei contribute to dissociable functions, we directly compared the functional contribution of the mediodorsal thalamus (MD) and of the anterior thalamic nuclei (ATN) in a new task assessing spatial goal-directed behavior in a cross-maze. Rats sustaining lesions of the mediodorsal or the anterior thalamus were trained to associate each of the two goal arms with a distinctive food reward.

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.

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.

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.

Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice.

Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR(4)), but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR(4) knock-out (KO) and wild-type (WT) mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR(4) control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR(4).

The intralaminar thalamic nuclei contribute to remote spatial memory.

Recent studies have shown that the anterior (ATN) and lateral thalamic nuclei (including the intralaminar nuclei; ILN/LT) play different roles in memory processes. These nuclei have prominent direct and indirect connections with the hippocampal system and/or the prefrontal cortex and may thus participate in the time-dependent reorganization of memory traces during systems-level consolidation. We investigated whether ATN or ILN/LT lesions in rats influenced acquisition and subsequent retrieval of spatial memory in a Morris water maze.

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.