(2R,6R)-HNK attenuates negative emotional behaviors and synaptic plasticity deficits via GluA1 in rats exposed to single prolonged stress and foot shock.

Heterogeneous and convoluted morphological features of dendritic spines in the human amygdaloid complex.

Migraine is a disorder of severe, recurrent headaches and debilitating sensory, cognitive and affective symptoms, often triggered by stress. Early life stress in childhood has been shown to increase the likelihood of migraine in adulthood in humans. Calcitonin-gene related peptide (CGRP) has been shown to reliably and acutely induce migraine or migraine-like behavior in both humans and rodent models. Here we investigate the impact of early life stress and CGRP on migraine-related neural circuitry in order to better understand the mechanisms by which early life stress predisposes neural circuitry to migraine brain network activity. We implemented an early life stress paradigm in the outbred strain of mice, CD1. We evaluated the impact of peripheral CGRP on migraine-like behavior and employed multi-site in vivo neurophysiology in freely behaving mice. A changepoint analysis was used to dissect differences in individual CGRP-induced responses. We found that early life stress exacerbated migraine-related behavioral and network physiology. CGRP alone caused disruptions in neural oscillatory activity across a network of brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), thalamus (Po, VPM, and MDthal), and parabrachial nucleus (PBN). We found that power across the network was lowered within 10 minutes of peripheral CGRP exposure, which was sustained for ~40-50 min. Coherence was mostly disrupted in amygdalar brain region pairings, and took on a shorter timecourse, with partial rescue of these responses by migraine abortive, sumatriptan. We found that early life stress exacerbated most of these responses, especially AMY-thalamic coherence pairings, although early life stress in the absence of CGRP demonstrated no impact on the network overall. We further identified individual mice with brain-network activity hypersusceptible to migraine. Our findings demonstrate that early life stress confers vulnerability to migraine, simultaneously impacting behavior and brain network activity responses to peripheral CGRP.

Receptor and cell-type-specific mechanisms in mesocortical dopamine circuits gate chronic pain and comorbid anxiodepression.

Sigma receptor ligands in selected affective disorders, psychoses, and addictions - a narrative review.

Major depressive disorder (MDD) is a severe mood disorder with genetic and environmental interactions. Subtypes with childhood trauma (CT) tend to have higher rates of suicide attempt (SA). The amygdala (AMY) and medial prefrontal cortex (mPFC) are integral to the neurocircuitry underlying emotional processing, with dysregulation of these regions being posited as a pathophysiological hallmark both in CT and SA. However, the specific neural mechanisms linking CT and SA are unclear. Here, we examined local neural oscillatory patterns and interregional connectivity within mPFC and AMY during sad emotion processing. 88 MDD patients (44 with CT, 44 without CT) and 44 healthy control (HC) participants underwent an emotion recognition task during magnetoencephalography (MEG) recording. Time-frequency analysis was used to examine inter-trial phase coherence (ITPC) and neural oscillatory power at bilateral mPFC and AMY. In addition, directed connectivity between mPFC and AMY was examined using Granger causality. MDD without CT demonstrated less ITPC at bilateral mPFC and bottom-up dysconnectivity from the AMY.R to the mPFC.R compared to HC. Theta power (bilateral mPFC and left AMY), ITPC (bilateral AMY and mPFC) and top-down functional connectivity from the mPFC.L to the AMY.L were reduced in MDD with CT relative to MDD without CT. Furthermore, the mPFC.L theta ITPC mediated the association between SA and CT. Overall, the results suggest that abnormal theta power modulation, phase coherence, and hypo-connectivity between the mPFC and AMY may underlie impaired sad emotion processing in MDD with CT, partially explaining the increased SA rate in this subgroup.

Working memory (WM) enables us to maintain and manipulate information over time, but how the brain organizes sequential information locally and across networks remains unclear. Recent work suggests that slow and fast theta oscillations serve different roles in memory, yet their distinct contributions to sequential WM are unknown. Based on evidence that the hippocampus (HC) and orbitofrontal cortex (OFC) support sequential WM and that slower theta cycles provide optimal temporal windows for organizing items in WM, we predicted that these regions would coordinate via slow theta dynamics. We analyzed intracranial EEG from the HC, OFC, and amygdala (AMY) in 21 neurosurgical patients (7 female, 13–54 years of age; M ± SD, 30 ± 11.2 years) performing a delayed match-to-sample WM task. We assessed phase locking between regions, phase-amplitude coupling within regions, and neuronal phase coding for slow (~1–4.5 Hz) and fast (~4.5–8 Hz) theta oscillations. We found significant slow and fast theta synchrony between all regions, but identical anatomical pathways produced opposing behavioral effects depending on oscillatory frequency, particularly during higher cognitive demand. Slow theta synchrony was associated with faster response times (RTs), while fast theta synchrony between HC and OFC hindered both accuracy and RTs. Unexpectedly, AMY modulated RT through demand-dependent slow theta synchrony, where AMY-OFC synchrony predicted faster RTs during maintenance and HC-AMY synchrony predicted faster RTs during higher cognitive demand. Sustained coupling between slow theta oscillations and high-frequency broadband activity within each region suggests that local organization coincides with beneficial network behavioral effects. These results establish a frequency-opponent mechanism in which theta oscillation frequencies determine whether HC-OFC circuits facilitate or impair sequential WM.

Down syndrome (DS), caused by trisomy 21, confers a near-universal risk for Alzheimer's disease (AD), yet individuals exhibit marked variability in cognitive decline, suggesting the presence of cellular mechanisms that modulate vulnerability and resilience. However, these mechanisms remain poorly defined in the human brain. Here, we integrate matched single-nucleus RNA-seq and ATAC-seq profiles from the prefrontal cortex (PFC) and amygdala (AMY) of age-matched individuals with DS with and without AD (DSAD), enabling direct comparison within a shared genetic background. We identify basal astrocytes in the PFC as a selectively vulnerable cell state in DSAD, characterized by both reduced abundance and coordinated transcriptional and regulatory reprogramming. This state exhibits a shift away from homeostatic support functions, with decreased cytokine signaling and lipid-handling programs, alongside increased steroid- and nuclear receptor-associated activity. Concomitantly, chromatin accessibility profiling reveals reduced engagement of immune- and stress-responsive transcription factor programs, including AP-1, STAT, and BACH families, with linked regulatory perturbations at loci such as ABCA1, DAB2IP, and IL1RAP. Together, these findings define a previously unrecognized astrocyte state marked by epigenetic constraint and diminished responsiveness to stress and inflammatory signals, distinguishing it from classical reactive astrocyte phenotypes. Our results nominate PFC basal astrocytes as a key locus of vulnerability in DSAD and suggest that failure to mount appropriate astrocyte responses, rather than overt activation alone, may contribute to neurodegenerative progression.

Effects of swLORETA Z-score neurofeedback in Z-coherence of the fronto-limbic circuit in patients with major depressive disorder.

Behavioral phenotype analysis highlights sleep heterogeneity and brain cellular activations in a mouse model of PTSD

Dendritic spines are postsynaptic specializations that mainly contact excitatory inputs and modulate a wide range of processes involving synaptic transmission and plasticity. Based on morphological features, they were classified into stubby, wide, thin, mushroom, ramified, and double spines. However, spines display other than these "classical" shapes, which are morphologically more convoluted and were initially called "atypical" spines. They have been much less studied and, then, worthy of investigation. Here, atypical (or, rather, multimorphic) spines, as well as complex dendritic protrusions, were examined using the Golgi method and after 2D and 3D image reconstructions in dendrites, cell bodies, and axon hillocks of several neuron types from both rats and humans. A variety of morphological features of complex dendritic protrusions and multimorphic spines were characterized in basket cells, Purkinje cells, brush neurons and granule cells of the cerebellum, in multipolar neurons of the inferior olivary nucleus, in multipolar neurons of the posterodorsal medial amygdaloid nucleus, in short-shaft pyramidal neurons of the hippocampus, in layers V-VI pyramidal and polymorphic neurons of the prefrontal cortex, and layers II-VI neurons of the anterior cingulate, precuneus, temporal, and occipital cortex. We provide evidence for the usual occurrence of these multimorphic spines, characterized by their heterogeneity in shape and size, and discuss the likely functional implications for synaptic processing, intraspine microdomains, compartmentalization features, and plasticity. Given their presence in rodents and humans, we also discuss the possible implications of multimorphic spines for more complex synaptic transmission across evolved neural circuits, laying the groundwork for future research.

Seeking warmth during infection is a sickness behaviour that contributes to the development of fever and is often accompanied by chills. However, the central mechanism underlying this behaviour remains unknown. We recently reported two ascending thermosensory neuronal pathways from the lateral parabrachial nucleus (LPB) of the pons that drive thermoregulatory behaviours in hot and cold environments: one pathway to the preoptic area (POA), a thermoregulatory centre, mediates heat avoidance, whereas the other to the central amygdaloid nucleus (CeA), a limbic emotion centre, mediates cold avoidance. Here we investigated the role of prostaglandin E2 (PGE2), a pyrogenic mediator produced during infection, in the LPB-mediated mechanism of thermoregulatory behaviour in rats. Thermal preference tests and in vivo physiological recordings revealed that PGE2 acting on the prostaglandin EP3 receptor (EP3R) in the LPB elicits behaviour that prefers warmth to a thermoneutral temperature, thereby contributing to an increase in body core temperature. However, it does not elicit brown adipose tissue thermogenesis, an autonomic febrile response. Notably, we discovered that EP3R-expressing LPB neurons (LPBEP3R neurons) project numerous axons to the CeA, but few to the POA. Functional neuronal tracing combined with immunostaining of Fos, a marker for neuronal activation, revealed that LPBEP3R→CeA neurons are activated by cold ambient temperature and constitute the majority of the cold-transmitting LPB→CeA neuronal population mediating cold avoidance. These results indicate that PGE2 action on LPBEP3R neurons during infection elicits warmth-seeking behaviour by augmenting their cold sensory transmission to the CeA, which potentially produces the unpleasant cold sensation of chills. KEY POINTS: Seeking warmth during infection is a commonly observed sickness behaviour that contributes to the development of fever, often accompanied by chills. Prostaglandin E2 (PGE2), a pyrogenic mediator, elicits warmth-seeking behaviour in rats by acting on prostaglandin EP3 receptor (EP3R)-expressing neurons in the lateral parabrachial nucleus (LPB) of the pons (LPBEP3R neurons). This PGE2 action does not elicit thermogenesis in brown adipose tissue, an autonomic febrile response. LPBEP3R neurons transmit cutaneous cold sensory signals to the limbic emotion centre, central amygdaloid nucleus (CeA), but scarcely innervate the thermoregulatory centre, preoptic area. These results indicate that PGE2 acting on LPBEP3R neurons during infection elicits warmth-seeking behaviour by augmenting cold sensory transmission to the CeA, which is a potential mechanism of chills.

While progress has been made in transcriptomic profiling of the human brain, functional characterization of brain regions and their interactions on the basis of regional protein expression remains limited. Here, we constructed a proteomic map from thirteen anatomical brain regions of eight cadaver donors to elucidate region-specific protein expression patterns and their implications for brain function. The results underscore the interconnectivity of the four cerebral lobes, suggesting facilitated information integration through large-scale neural networks. We propose a three-module framework (cortical integration module [frontal lobe, temporal lobe, parietal lobe, occipital lobe], limbic-relay network [amygdaloid nucleus, hippocampus, thalamus/hypothalamus], and midline regulatory axis [thalamus/hypothalamus, corpus callosum, ventricles, optic chiasm]) and provide molecular evidence supporting the potential involvement of the midline regulatory axis, brainstem, and cerebellum in higher-order cognitive functions. The midline regulatory axis may play a critical but underexplored role in neurodevelopment, interregional signaling, and structural homeostasis, potentially through efficient synaptic function, energy metabolism, and extracellular matrix integrity. This analysis may enhance the understanding of brain physiology and highlight the need to integrate proteomic and transcriptomic approaches in the study of brain function and neurological disorders.

The impact of maternal separation stress on the CRFergic system in the extended amygdala and its relevance to acute stress-induced ethanol consumption in mice.

An explainable predictive machine learning model reveals ARRB2 as a key gene in post-traumatic stress disorder: A GEO database study.

Olfactory information directly reaches the amygdala through the olfactory cortex, without the involvement of thalamic areas, unlike other sensory systems. The anterior cortical amygdaloid nucleus (ACo) is one of the olfactory cortices that receives olfactory sensory input and is part of the olfactory cortical amygdala, which relays olfactory information to the amygdala. To examine its electrophysiological features, we recorded individual ACo neurons during the odor-guided go/no-go task to obtain a water reward. Many ACo neurons exhibited odor-evoked go cue-preferred activity during the late phase of nose-poking supporting the population dynamics that differentiate go/no-go responses before executing the odor-evoked behaviors. We observed two types of neurons with different anticipation signals: one neuron type exhibited gradual increases of activity toward reward delivery, while another type exhibited a phasic go cue-preferred activity during nose-poking as well as another phasic anticipatory activity for rewards. These results suggest that the ACo may be involved in reward-related behavioral learning by associating the olfactory information with reward anticipation.

Sex differences in brain function critically influence vulnerability to stress-related disorders such as anxiety and depression. Stress relief, defined as a positive emotional state following the termination of a threat, has been proposed as a natural reward promoting resilience. However, little is known about sex differences in stress relief behavior and the underlying neural mechanisms involved. Adult male and female C57BL/6J mice were subjected to a conditioned place preference (CPP) paradigm to evaluate stress relief responses following acute restraint stress. Estrous cycle stages in females were monitored during the test day to exclude hormonal effects. Whole-brain neuronal activity was assessed using large-scale c-Fos mapping to identify sex-specific neural correlates of stress relief. To establish causality, chemogenetic manipulations were performed by bilaterally expressing hM3Dq or hM4Di DREADDs in the central amygdala (CeA), followed by clozapine-N-oxide administration to selectively activate or inhibit CeA neurons during the behavioral test. We found that male mice exhibited a robust stress relief response, whereas female mice failed to display stress relief, independent of stress intensity or the estrous cycle. c-Fos mapping revealed CeA neuronal inactivation in males but not females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons facilitated stress relief in females. These data highlight the sex-specific role of CeA neurons in regulating stress relief, with inactivation promoting relief in males and inhibition enabling relief in females. These findings may provide a neural basis for understanding sex-specific mechanisms of stress relief and offer insights into the circuit-level origins of sex-biased vulnerability to stress-related psychiatric disorders. Male mice exhibited robust stress relief responses, whereas females failed to display stress relief. The absence of stress relief in females was independent of stress intensity and estrous cycle stage. Whole-brain c-Fos mapping revealed sex-specific neural activation patterns, with CeA neurons inactivated in males but not in females during stress relief. Chemogenetic activation of CeA neurons abolished stress relief in males, whereas inhibition of CeA neurons enabled stress relief in females. Exploring sex differences in the brain is important for understanding the effects of such differences in stress-related disorders characterized by sex bias, as well as their therapeutic implications. In this manuscript, we examined sex differences in stress relief, a positive emotion triggered by the absence of an expected threat or the termination of an ongoing threat, as well as its potential mechanism. Our findings revealed sex variation in the stress relief response, as female mice did not show a stress relief response, which was independent of stress intensity or estrous cycle fluctuations. By determining neuronal activation in the mouse brain following a stress relief assay, we found that CeA neurons are inactivated during this paradigm in male mice but not in female mice. Moreover, chemogenetic activation of CeA neurons abolished the stress relief responses in male mice, whereas chemogenetic inactivation of CeA neurons facilitated the stress relief responses in female mice. We speculated that CeA neurons might play a key role in the sexually dimorphic stress relief response in mice. Hence, it is important to consider sex differences in both preclinical and clinical research studies that attempt to understand the mechanism related to stress relief.

Chronic stress is epidemiologically linked to metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. In mice exposed to chronic restraint stress (CRS), we observed weight-independent hepatic steatosis with marked degeneration of sympathetic fibers. Stress elevated circulating norepinephrine levels but blunted hepatic β-adrenergic/cyclic adenosine monophosphate (cAMP) signaling accompanied by downregulation of β3-adrenergic receptor (β3-AR), indicating hepatic catecholamine resistance. Blocking hepatic sympathetic input prevented stress-aggravated steatosis and restored β-adrenergic signaling, whereas pharmacologic activation of β3-AR with mirabegron alleviated stress-induced lipid accumulation. Pseudorabies virus retrograde tracing and neuronal circuit interrogation further showed that projection from the medial central amygdaloid nucleus (CeM) to paraventricular hypothalamic corticotropin-releasing hormone (CRHPVH) neurons mediated stress induced hepatic steatosis. Together, these results reveal a CeM-CRHPVH-hepatic sympathetic axis that couples central stress signaling to peripheral β-adrenergic desensitization and lipid dysregulation, thereby suggesting a potential therapeutic strategy for stress-related MASLD.

The neural pathways and genetic substrates of non-suicidal self-injury as a "sensation of pain" addiction in drug-naïve depressed adolescents.

Familial hypercholesterolemia, caused by mutations in the low-density lipoprotein receptor (LDLr), is associated with cognitive and affective disturbances. However, sex differences in the impact of LDLr deficiency on anxiety and social behaviors remain poorly characterized. Male and female LDLr⁻/⁻ and wild-type (WT) C57BL/6 mice (4-5months old) underwent a battery of behavioral tests assessing locomotion, anxiety-like behavior (open field, elevated plus maze, marble-burying test), and sociability (social interaction and three-chamber test). Serum cholesterol levels and catechol-O-methyltransferase (COMT) levels in the prefrontal cortex (PFC) and amygdala (AMY) were subsequently analyzed by Western blotting. Both male and female LDLr⁻/⁻ mice displayed marked hypercholesterolemia relative to WT controls. Female LDLr⁻/⁻ mice exhibited hyperlocomotion and reduced anxiety-like behavior in multiple tasks. Both sexes demonstrated increased sociability, although with test- and sex-dependent variations. Neurochemical analysis revealed a selective reduction of COMT in the PFC of LDLr⁻/⁻ females, suggesting sex-specific dopaminergic modulation underlying the behavioral phenotypes. LDLr deficiency induced sex-dependent changes in locomotor, anxiety-related, and social behaviors, accompanied by altered COMT expression in corticolimbic regions. These findings reveal an association between LDL receptors, dopaminergic regulation, and socio-emotional behaviors, emphasizing the relevance of social characterization in the neurobehavioral assessment of dyslipidemia.