In relentless pursuit of the white whale: A role for the ventral midline thalamus in behavioral flexibility and adaption?

The reuniens (Re) nucleus is located in the ventral midline thalamus. It has fostered increasing interest, not only for its participation in a variety of cognitive functions (e.g., spatial working memory, systemic consolidation, reconsolidation, extinction of fear or generalization), but also for its neuroanatomical positioning as a bidirectional relay between the prefrontal cortex (PFC) and the hippocampus (HIP). In this review we compile and discuss recent studies having tackled a possible implication of the Re nucleus in behavioral flexibility, a major PFC-dependent executive function controlling goal-directed behaviors. Experiments considered explored a possible role for the Re nucleus in perseveration, reversal learning, fear extinction, and set-shifting. They point to a contribution of this nucleus to behavioral flexibility, mainly by its connections with the PFC, but possibly also by those with the hippocampus, and even with the amygdala, at least for fear-related behavior. As such, the Re nucleus could be a crucial crossroad supporting a PFC-orchestrated ability to cope with new, potentially unpredictable environmental contingencies, and thus behavioral flexibility and adaption.

Disconnecting prefrontal cortical neurons from the ventral midline thalamus: Loss of specificity due to progressive neural toxicity of an AAV-Cre in the rat thalamus.

BACKGROUND: The thalamic reuniens (Re) and rhomboid (Rh) nuclei are bidirectionally connected with the medial prefrontal cortex (mPFC) and the hippocampus (Hip). Fiber-sparing N-methyl-D-aspartate lesions of the ReRh disrupt cognitive functions, including persistence of certain memories. Because such lesions irremediably damage neurons interconnecting the ReRh with the mPFC and the Hip, it is impossible to know if one or both pathways contribute to memory persistence. Addressing such an issue requires selective, pathway-restricted and direction-specific disconnections. NEW METHOD: A recent method associates a retrograde adeno-associated virus (AAV) expressing Cre recombinase with an anterograde AAV expressing a Cre-dependent caspase, making such disconnection feasible by caspase-triggered apoptosis when both constructs meet intracellularly. We injected an AAVrg-Cre-GFP into the ReRh and an AAV5-taCasp into the mPFC. As expected, part of mPFC neurons died, but massive neurotoxicity of the AAVrg-Cre-GFP was found in ReRh, contrasting with normal density of DAPI staining. Other stainings demonstrated increasing density of reactive astrocytes and microglia in the neurodegeneration site. COMPARISON WITH EXISTING METHODS: Reducing the viral titer (by a 4-fold dilution) and injection volume (to half) attenuated toxicity substantially, still with evidence for partial disconnection between mPFC and ReRh. CONCLUSIONS: There is an imperative need to verify potential collateral damage inherent in this type of approach, which is likely to distort interpretation of experimental data. Therefore, controls allowing to distinguish collateral phenotypic effects from those linked to the desired disconnection is essential. It is also crucial to know for how long neurons expressing the Cre-GFP protein remain operational post-infection.

Inhibition of the ventral midline thalamus does not alter encoding, short-term holding or retrieval of spatial information in rats performing a water-escape working memory task.

Working memory (WM) is a function operating in three successive phases: encoding (sample trial), holding (delay), and retrieval (test trial) of information. Studies point to a possible implication of the thalamic reuniens nucleus (Re) in spatial WM (SWM). In which of the aforementioned 3 phases the Re has a function is largely unknown. Recently, in a delayed SWM water-escape task, we found that performance during the retrieval trial correlated positively with c-Fos expression in the Re nucleus, suggesting participation in retrieval. Here, we used the same task and muscimol (MUSC) inhibition or DREADD(hM4Di)-mediated inhibition of the Re during information encoding, right thereafter (thereby affecting the holding phase), or during the retrieval trial. A 6-hour delay separated encoding from retrieval. Concerning SWM, MUSC in the Re nucleus did not alter performance, be it during or after encoding, or during evaluation. CNO administered before encoding in DREADD-expressing rats was also ineffective, although CNO-induced inhibition disrupted set shifting performance, as found previously (Quet et al., Brain Struct Function 225, 2020), thereby validating DREADD efficiency. These findings are the first that do not support an implication of the Re nucleus in SWM. As most previous studies used T-maze alternation tasks, which carry high proactive interference risks, an important question to resolve now is whether the Re nucleus is required in (T-maze alternation) tasks using very short information-holding delays (seconds to minutes), and less so in other short-term spatial memory tasks with longer information holding intervals (hours) and therefore reduced interference risks.

Early memory deficits and extensive brain network disorganization in the AppNL-F/MAPT double knock-in mouse model of familial Alzheimer's disease.

A critical challenge in current research on Alzheimer's disease (AD) is to clarify the relationship between network dysfunction and the emergence of subtle memory deficits in itspreclinical stage. The AppNL-F/MAPT double knock-in (dKI) model with humanized ß-amyloid peptide (Aß) and tau was used to investigate both memory and network dysfunctions at an early stage. Young male dKI mice (2 to 6 months) were tested in three tasks taxing different aspects of recognition memory affected in preclinical AD. An early deficit first appeared in the object-place association task at the age of 4 months, when increased levels of ß-CTF and Aß were detected in both the hippocampus and the medial temporal cortex, and tau pathology was found only in the medial temporal cortex. Object-place task-dependent c-Fos activation was then analyzed in 22 subregions across the medial prefrontal cortex, claustrum, retrosplenial cortex, and medial temporal lobe. Increased c-Fos activation was detected in the entorhinal cortex and the claustrum of dKI mice. During recall, network efficiency was reduced across cingulate regions with a major disruption of information flow through the retrosplenial cortex. Our findings suggest that early perirhinal-entorhinal pathology is associated with abnormal activity which may spread to downstream regions such as the claustrum, the medial prefrontal cortex and ultimately the key retrosplenial hub which relays information from frontal to temporal lobes. The similarity between our findings and those reported in preclinical stages of AD suggests that the AppNL-F/MAPT dKI model has a high potential for providing key insights into preclinical AD.