The renin-angiotensin system (RAS), traditionally recognized for cardiovascular and renal regulation, has emerged as a critical mechanistic player in neuropsychiatric pathophysiology. The brain possesses its own independent RAS with components located throughout limbic regions, cortical areas, and monoaminergic circuits that are essential for mood, cognition, and behavior. Within this framework, angiotensin II (Ang II), acts primarily through angiotensin II type 1 receptors (AT1Rs), orchestrates pathological cascades including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-mediated oxidative stress and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-driven neuroinflammation which converge to disrupt synaptic plasticity, impair neurogenesis, compromise blood-brain barrier (BBB) integrity, and dysregulate hypothalamic-pituitary-adrenal axis (HPA) axis- all contributing to major depression, anxiety disorders, schizophrenia, and bipolar disorder. However, the brain also contains protective RAS pathways, including angiotensin II Type 2 receptors (AT2Rs) and the angiotensin-converting enzyme 2/ Angiotensin-(1-7)/ Mas receptor (ACE2/Ang-(1-7)/MasR) axis, which offer neuroprotective effects that counterbalance these damaging processes. Therefore, targeting the RAS may represent a paradigm shift in neuropsychiatric treatment, as medications that modulate this system- including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)- show significant promise by addressing the fundamental molecular mechanisms driving mental illness rather than merely managing symptoms. Ultimately, this approach bridges peripheral physiological dysregulation with central nervous system (CNS) dysfunction, offering a precision medicine strategy that targets the root biological causes of neuropsychiatric disorders and opens new therapeutic avenues for patients who may not respond adequately to conventional treatments.

Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.

Neuropathic pain (NP), arising from lesions or dysfunction of the somatosensory system, remains a major clinical challenge due to its subjective and multidimensional nature. Traditional pain assessments rely on self‑report scales, which lack objectivity and reproducibility. Electroencephalography (EEG), with its high temporal resolution and accessibility, provides a promising avenue for identifying candidate neurophysiological biomarkers of pain. The current narrative review integrates mechanistic insights and electrophysiological evidence to delineate EEG alterations in NP. Resting‑state θ increases and dominant‑frequency slowing are relatively recurrent in chronic NP, whereas α‑, β‑ and γ‑band findings remain heterogeneous. Network analyses further reveal aberrant prefrontal‑limbic and sensorimotor connectivity, as well as altered cross‑frequency coupling, but the direction and topology of these findings remain dependent on the patient population, recording configuration and analytical metric. Advances in computational EEG analysis, graph theory and machine learning are facilitating exploration of objective, individualized pain assessment frameworks. Emerging portable EEG and multimodal approaches may provide opportunities for future clinical translation. Overall, EEG offers a feasible and dynamic method to bridge subjective pain perception with measurable neurophysiological signatures, paving the way toward precision diagnostics and neuromodulation in NP.

Posttraumatic stress disorder (PTSD) remains difficult to treat, with 30-50% of patients retaining their diagnosis after first-line trauma-focused psychotherapies. Body-based therapies (BBTs) and transcranial magnetic stimulation (TMS) have each shown preliminary benefit for PTSD but have not yet been studied in combination. To our knowledge, this is the first proposal to integrate these modalities as a combined therapeutic approach. PTSD involves disrupted coordination across multiple levels of neural organization, from cortical regulatory networks to limbic threat circuits and autonomic systems. BBTs are theorized to engage bottom-up processes, including autonomic regulation and interoceptive recalibration, while TMS operates through top-down modulation of prefrontal-limbic circuitry and large-scale network connectivity. This complementarity suggests that a combined approach could engage a broader range of PTSD-related dysfunction than either intervention alone. This article reviews the evidence and proposed mechanisms for each modality, places both within current models of PTSD neurocircuitry, and examines potential pathways of interaction including neuroplasticity priming and autonomic stabilization. Important risks are also addressed, including autonomic destabilization, unknown optimal sequencing, and the open question of whether mechanistically distinct treatments produce additive benefits. The case for combining BBTs and TMS is presented as a hypothesis warranting further investigation.

Rodent models of human adolescent binge drinking persistently reduce adult neurogenesis and induce innate immune signaling cascades, suggesting long-lasting dysfunction in the hippocampal neurogenic niche. Nevertheless, many neuroprogenitors survive, and the impact of adolescent ethanol on the mature phenotype of these surviving neurons is unknown, resulting in an unstudied cellular population that could impact hippocampal function. To label a cohort of immature neurons, we used doublecortin-CreERT2 transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, resulting in tamoxifen-induced labeling of newborn neurons. Female offspring underwent adolescent intermittent ethanol (AIE) (5 g/kg ethanol or water by gavage, 2-day-on/2-day-off from postnatal day 29-58 ± 1), followed by a multi-month ethanol-free period. AIE increased dendritic branch width and cellular migratory distance, increased hilar axonal varicosities, reduced dendritic spine density, and shifted action potential generation with escalating current injections in tdTomato+ cells. Although tdTomato+ expression was also decreased in AIE relative to CON mice, there was no significant change in the number of tdTomato+ somata. AIE also reduced microglial territory in the polymorphic and molecular layers despite no change in cell number. Furthermore, microglia entwined in the dendritic trees of surviving adolescent neuroprogenitors exhibited increased sphericity, potentially indicative of a shift towards a more reactive morphological phenotype. Surviving neuroprogenitors exhibited no changes in labeling of the vesicular acetylcholine transporter, despite robust cholinergic innervation proximal to the mature dendritic tree that reduced rapidly with increasing distance from dendritic arbors. These results suggest that AIE causes lasting changes in the architectural and physiological phenotype of surviving adolescent neuroprogenitors, which may be related to disrupted neuronal-microglial dynamics and have critical consequences for both hippocampal circuitry and function.

Distress sharing within an ingroup instinctively motivates caregiving-like prosocial behavior in social animals and humans, yet how aversive social stimuli paradoxically trigger such behavior remains unclear. Here, we show that stress-state matching in observer mice elicits caregiving-like behaviors (allogrooming and injury-targeted allolicking) toward cagemates in pain, resulting in synchronized social buffering. Importantly, we identify that the excitation of vasopressin receptor 1a-expressing (V1aR-expressing) neurons in the central medial amygdala (CeM) underlies both emotional-state matching and subsequent allogrooming/allolicking. This excitation is accomplished by arginine vasopressin (AVP) release from presynaptic terminals of the hypothalamic paraventricular nucleus (PVN) to act specifically on postsynaptic V1aR in the CeM. The CeMV1aR neurons then project to the ventral tegmental area (VTA) to drive caregiving-like actions through positive reinforcement, manifested as prosocial preference and recurrent allogrooming/allolicking, and to produce anxiolysis in the caregiver. Collectively, we unravel a dedicated trisynaptic PVNAVP-CeMV1aR-VTA circuit driving and gating caregiving-like behaviors and advance the mechanistic understanding of AVP-V1aR signaling in prosociality.

The brain's ability to consolidate a wide range of memories while maintaining their distinctiveness across experiences remains poorly understood. Sharp-wave ripples, neural oscillations that occur predominantly within CA1 of the hippocampus during immobility and sleep, have been shown to play a critical role in the consolidation process. More recently, evidence has uncovered functional heterogeneity of pyramidal neurons within distinct sublayers of CA1 that display unique properties during ripples, potentially contributing to memory specificity. Despite this, it remains unclear exactly how ripples shift the activity of CA1 neuronal populations to accommodate the consolidation of specific memories and how sublayer differences manifest. Here, we studied interactions between the anterior cingulate cortex (ACC) and CA1 neurons during ripples and discovered a reorganization of their communication following learning. Specifically, using a generalized linear model decoder, we demonstrated the pre-existence of ACC-to-CA1 communication, which is weakened during post-training sleep following learning, suggesting that ACC activity reallocates the contribution of CA1 neurons during memory formation. Interestingly, the reorganization appeared unique for a subset of CA1 superficial (CA1sup) neurons that were task inactive, whereas communication between the ACC and CA1deep neurons remained largely stable across pre- and post-training sleep. Consistent with this sublayer-selective reorganization, we found that optogenetic stimulations of the ACC preferentially suppressed CA1sup neurons while activating a unique subset of CA1 interneurons. Overall, these findings highlight an important role of the ACC in rebalancing CA1 neuronal populations' contribution in learning and memory consolidation.

The basolateral amygdala complex (BNC) plays an important role in learning, memory, motivation, and social behaviour, with its dysfunction implicated in a wide variety of psychiatric disorders. Despite being one of the most intensely researched areas of the brain, much is still unknown about its microanatomical structure and function, relationships and evolutionary origins. In this review, we offer a multidisciplinary approach through the lens of comparative anatomy and evolutionary developmental studies to provide a better understanding of the anatomical and functional relationship between the amygdala and cortex in memory, learning, and social behaviour. Particular attention is paid to the evolutionary origin of pallial areas across amniotes, as well as homology between principal neurons, cortical layers, BNC nuclei, and connectivity between these areas. We argue that the basolateral amygdala complex functions as an early form of the mammalian neocortex. This theory will help to further the understanding of amygdala and cortex function in both health and psychiatric disease.

To investigate whether epiregulin (EREG) mitigates type 2 diabetes-associated cognitive dysfunction (T2DM-ACD) by inhibiting hippocampal ferroptosis via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. T2DM mice received EREG or vehicle for 4 weeks. Cognitive function was assessed by Morris water maze. Hippocampal neuronal damage was evaluated by Nissl staining, and ferroptosis-related protein expression was assessed by immunofluorescence. Transcriptomic profiling was performed by RNA sequencing in HT22 cells under control, high-glucose, and EREG-treated conditions. HT22 hippocampal neurons were exposed to high glucose with or without EREG, and the Nrf2 inhibitor ML385 was added to verify pathway dependency. Mitochondrial ultrastructure was observed by transmission electron microscopy. Ferroptosis-related indices, including lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), glutathione (GSH), and intracellular ferrous iron (Fe[2][+]) levels, were measured by flow cytometry and biochemical assays. The expression of Nrf2 pathway proteins, including Nrf2, solute carrier family 7 member 11 (SLC7A11), and GPX4, was analyzed by western blotting. In vivo, EREG ameliorated cognitive deficits and hippocampal neuronal damage in T2DM mice, restoring glutathione peroxidase 4 (GPX4) and suppressing cyclooxygenase-2 (COX2) expression. In vitro, EREG reversed high glucose-induced transcriptomic alterations, enriched antioxidant pathways, preserved mitochondrial integrity, reduced lipid ROS, MDA, and Fe[2][+] accumulation, and restored GSH levels. Mechanistically, EREG activated the Nrf2-SLC7A11-GPX4 signaling axis, and these effects were reversed by the Nrf2 inhibitor ML385. EREG protects against T2DM-ACD by inhibiting hippocampal ferroptosis in an Nrf2-dependent manner, representing a potential therapeutic candidate.