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During non-rapid eye movement (NREM) sleep, neural ensembles in the entorhinal-hippocampal circuit responsible for encoding recent memories undergo reactivation to facilitate the process of memory consolidation. This reactivation is widely acknowledged as pivotal for the formation of stable memory and its impairment is closely associated with memory dysfunction. To date, the neural mechanisms driving the reactivation of neural ensembles during NREM sleep remain poorly understood. Here, we show that the neural ensembles in the medial entorhinal cortex (MEC) that encode spatial experiences exhibit reactivation during NREM sleep. Notably, this reactivation consistently coincides with isolated theta waves. In addition, we found that the nucleus reuniens (RE) in the midline thalamus exhibits typical theta waves during NREM sleep, which are highly synchronized with those occurring in the MEC in male mice. Closed-loop optogenetic inhibition of the RE-MEC pathway specifically suppressed these isolated theta waves, resulting in impaired reactivation and compromised memory consolidation following a spatial memory task in male mice. The findings suggest that theta waves originating from the ventral midline thalamus play a role in initiating memory reactivation and consolidation during sleep., (© 2024. The Author(s).)

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The mechanisms that confer cognitive resilience to Alzheimer's Disease (AD) are not fully understood. Here, we describe a neural circuit mechanism underlying this resilience in a familial AD mouse model. In the prodromal disease stage, interictal epileptiform spikes (IESs) emerge during anesthesia in the CA1 and mPFC regions, leading to working memory disruptions. These IESs are driven by inputs from the thalamic nucleus reuniens (nRE). Indeed, tonic deep brain stimulation of the nRE (tDBS-nRE) effectively suppresses IESs and restores firing rate homeostasis under anesthesia, preventing further impairments in nRE-CA1 synaptic facilitation and working memory. Notably, applying tDBS-nRE during the prodromal phase in young APP/PS1 mice mitigates age-dependent memory decline. The IES rate during anesthesia in young APP/PS1 mice correlates with later working memory impairments. These findings highlight the nRE as a central hub of functional resilience and underscore the clinical promise of DBS in conferring resilience to AD pathology by restoring circuit-level homeostasis., (© 2023. The Author(s).)

Traumatic events result in vivid and enduring fear memories. Suppressing the retrieval of these memories is central to behavioral therapies for pathological fear. The medial prefrontal cortex (mPFC) and hippocampus (HPC) have been implicated in retrieval suppression, but how mPFC-HPC activity is coordinated during extinction retrieval is unclear. Here we show that after extinction training, coherent theta oscillations (6-9 Hz) in the HPC and mPFC are correlated with the suppression of conditioned freezing in male and female rats. Inactivation of the nucleus reuniens (RE), a thalamic hub interconnecting the mPFC and HPC, reduces extinction-related Fos expression in both the mPFC and HPC, dampens mPFC-HPC theta coherence, and impairs extinction retrieval. Conversely, theta-paced optogenetic stimulation of RE augments fear suppression and reduces relapse of extinguished fear. Collectively, these results demonstrate a role for RE in coordinating mPFC-HPC interactions to suppress fear memories after extinction., (© 2023. Springer Nature Limited.)

Episodic memory-based decision-making requires top-down medial prefrontal cortex and hippocampal interactions. This integrated prefrontal-hippocampal memory state is thought to be organized by synchronized network oscillations and mediated by connectivity with the thalamic nucleus reuniens (RE). Whether and how the RE synchronizes prefrontal-hippocampal networks in memory, however, remains unknown. Here, we recorded local field potentials from the prefrontal-RE-hippocampal network while rats engaged in a nonspatial sequence memory task, thereby isolating memory-related activity from running-related oscillations. We found that synchronous prefrontal-hippocampal beta bursts (15-30 Hz) dominated during memory trials, whereas synchronous theta activity (6-12 Hz) dominated during non-memory-related running. Moreover, RE beta activity appeared first, followed by prefrontal and hippocampal synchronized beta, suggesting that prefrontal-hippocampal beta could be driven by the RE. To test whether the RE is capable of driving prefrontal-hippocampal beta synchrony, we used an optogenetic approach (retroAAV-ChR2). RE activation induced prefrontal-hippocampal beta coherence and reduced theta coherence, matching the observed memory-driven network state in the sequence task. These findings are the first to demonstrate that the RE contributes to memory by driving transient synchronized beta in the prefrontal-hippocampal system, thereby facilitating interactions that underlie memory-based decision-making., (© 2023. The Author(s).)

Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLM CA ) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLM CA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLM CA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLM CA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLM CA -pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLM CA -pPVT-NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.

Myocardial infarction is the leading cause of death worldwide. Restoration of blood flow rescues myocardium but also causes ischemia-reperfusion injury. Here, we show that in a mouse model of chronic neuropathic pain, ischemia-reperfusion injury following myocardial infarction is reduced, and this cardioprotection is induced via an anterior nucleus of paraventricular thalamus (PVA)-dependent parasympathetic pathway. Pharmacological inhibition of extracellular signal-regulated kinase activation in the PVA abolishes neuropathic pain-induced cardioprotection, whereas activation of PVA neurons pharmacologically, or optogenetic stimulation, is sufficient to induce cardioprotection. Furthermore, neuropathic injury and optogenetic stimulation of PVA neurons reduce the heart rate. These results suggest that the parasympathetic nerve is responsible for this unexpected cardioprotective effect of chronic neuropathic pain in mice.Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.

Many fearful expectations are shaped by observation of aversive outcomes to others. Yet, the neurochemistry regulating social learning is unknown. Previous research has shown that during direct (Pavlovian) threat learning, information about personally experienced outcomes is regulated by the release of endogenous opioids, and activity within the amygdala and periaqueductal gray (PAG). Here we report that blockade of this opioidergic circuit enhances social threat learning through observation in humans involving activity within the amygdala, midline thalamus and the PAG. In particular, anticipatory responses to learned threat cues (CS) were associated with temporal dynamics in the PAG, coding the observed aversive outcomes to other (observational US). In addition, pharmacological challenge of the opioid receptor function is classified by distinct brain activity patterns during the expression of conditioned threats. Our results reveal an opioidergic circuit that codes the observed aversive outcomes to others into threat responses and long-term memory in the observer.