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Journal of Cerebral Blood Flow and... Mar 2023A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to...
A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.
Topics: Rats; Animals; Hippocampus; Fear; Thalamic Nuclei; Cell Death; Heart Arrest; Exercise
PubMed: 36369732
DOI: 10.1177/0271678X221137539 -
Nature Communications Mar 2023Binge alcohol consumption induces discrete social and arousal disturbances in human populations that promote increased drinking and accelerate the progression of Alcohol...
Binge alcohol consumption induces discrete social and arousal disturbances in human populations that promote increased drinking and accelerate the progression of Alcohol Use Disorder. Here, we show in a mouse model that binge alcohol consumption disrupts social recognition in females and potentiates sensorimotor arousal in males. These negative behavioral outcomes were associated with sex-specific adaptations in serotonergic signaling systems within the lateral habenula (LHb) and the bed nucleus of the stria terminalis (BNST), particularly those related to the receptor 5HT. While both BNST and LHb neurons expressing this receptor display potentiated activation following binge alcohol consumption, the primary causal mechanism underlying the effects of alcohol on social and arousal behaviors appears to be excessive activation of LHb neurons. These findings may have valuable implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brain's serotonin system.
Topics: Humans; Male; Female; Mice; Animals; Alcoholism; Binge Drinking; Serotonin; Neurons; Alcohol Drinking; Arousal; Ethanol; Septal Nuclei
PubMed: 37002196
DOI: 10.1038/s41467-023-36808-2 -
Current Biology : CB Oct 2021Discrimination between predictive and non-predictive threat stimuli decreases as threat intensity increases. The central mechanisms that mediate the transition from...
Discrimination between predictive and non-predictive threat stimuli decreases as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identify several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted "U" relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.
Topics: Dorsal Raphe Nucleus; Dynorphins; Receptors, Opioid, kappa; Septal Nuclei; Ventral Tegmental Area
PubMed: 34388372
DOI: 10.1016/j.cub.2021.07.047 -
Cell Reports Jul 2023The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic...
The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic stress, but the roles of DA network of dBNST in chronic stress-induced emotional disorders remain unclear. We examine the role of dBNST Drd1 and Drd2 neurons in post-weaning social isolation (PWSI)-induced behavior deficits. We find that male, but not female, PWSI rats exhibit negative emotional phenotypes and the increase of excitability and E-I balance of dBNST Drd2 neurons. More importantly, hypofunction of dBNST Drd2 receptor underlies PWSI-stress-induced male-specific neuronal plasticity change of dBNST Drd2 neurons. Furthermore, chemogenetic activation of dBNST Drd2 neurons is sufficient to induce anxiogenic effects, while Kir4.1-mediated chronic inhibition of dBNST Drd2 neurons ameliorate PWSI-induced anxiety-like behaviors. Our findings reveal an important neural mechanism underlying PWSI-induced sex-specific behavioral abnormalities and potentially provide a target for the treatment of social stress-related emotional disorder.
Topics: Female; Male; Rats; Animals; Anxiety; Neurons; Septal Nuclei; Stress, Psychological; Social Isolation; Receptors, Dopamine D2
PubMed: 37453056
DOI: 10.1016/j.celrep.2023.112799 -
ENeuro 2022Fear and anxiety can be described as emotional and physical responses to predictable and unpredictable threats. While the amygdala is necessary for context and cued fear...
Fear and anxiety can be described as emotional and physical responses to predictable and unpredictable threats. While the amygdala is necessary for context and cued fear conditioning, the bed nucleus of the stria terminalis (BNST) is important for anxiety-like behavior and conditioned responses to diffuse and/or unpredictable threats. However, we still lack knowledge about how the BNST and amygdala nuclei act in coordination. Moreover, the incidence of anxiety disorders and posttraumatic stress disorder (PTSD) is substantially higher in women than in men, but most studies of fear conditioning are conducted in male rodents. Here, we asked whether the BNST and the lateral, basal, and central nuclei of the amygdala are active during the expression of fear conditioning in male and female rats using FOS immunohistochemistry. We first show that the BNST is indeed involved in context fear expression in males, but not in females. The lateral amygdala was active in both sexes during context fear expression. We next trained animals using tone cues paired with an unconditioned stimulus (US), or tone cues which were unpaired with the US, and thus nonpredictive. Females displayed greater fear expression to these unpaired tones than males. FOS was upregulated in both the BNST and the basal amygdala during fear expression to unpaired tones in both sexes. The differential processing of fear responses by males and females highlights the need to acknowledge sex differences in conditioned fear memory.
Topics: Amygdala; Animals; Conditioning, Classical; Cues; Female; Male; Rats; Septal Nuclei; Sex Characteristics
PubMed: 34911788
DOI: 10.1523/ENEURO.0233-21.2021 -
Brain Circulation 2021Cholinergic efferent networks located from the medial septal nucleus to the hippocampus play a pivotal role in learning and memory outcomes by generating regular theta... (Review)
Review
Cholinergic efferent networks located from the medial septal nucleus to the hippocampus play a pivotal role in learning and memory outcomes by generating regular theta rhythms that enhance information retention. Hippocampal cholinergic neurostimulating peptide (HCNP), derived from the N-terminus of HCNP precursor protein (HCNP-pp), promotes the synthesis of acetylcholine in the medial septal nuclei. HCNP-pp deletion significantly reduced theta power in CA1 possibly due to lower levels of choline acetyltransferase-positive axons in CA1 stratum oriens, suggesting cholinergic disruptions in the septo-hippocampal system. This review also explores HCNP as a potent cholinergic regulator in the septo-hippocampal network while also examining the limitations of our understanding of the neurostimulating peptide.
PubMed: 34084974
DOI: 10.4103/bc.bc_14_21 -
Journal of Clinical Neurology (Seoul,... Nov 2022We aimed to determine 1) the frequency of mammillary body (MB) atrophy in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS), 2) the clinical...
BACKGROUND AND PURPOSE
We aimed to determine 1) the frequency of mammillary body (MB) atrophy in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS), 2) the clinical significance of MB atrophy, and 3) the association between MB atrophy and volume changes in other subcortical limbic structures.
METHODS
We enrolled 69 patients with pathologically confirmed TLE with HS, who underwent a standard anterior temporal lobectomy, as well as 40 healthy controls. We used the FreeSurfer deep-learning tool of U-Net to obtain the volumes of the subcortical limbic structures, including the MB, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens. MB atrophy was considered to be present when the MB volume was decreased relative to the healthy controls.
RESULTS
MB atrophy was present in 18 (26.1%) of the 69 patients with TLE and HS. Among the clinical characteristics, the mean age at seizure onset was higher (25.5 vs. 15.9 years, =0.027) and the median duration of epilepsy was shorter (149 vs. 295 months, =0.003) in patients with than without MB atrophy. The basal forebrain (0.0185% vs. 0.0221%, =0.004) and septal nuclei (0.0062% vs. 0.0075%, =0.003) in the ipsilateral hemisphere of HS were smaller in the patients with MB atrophy.
CONCLUSIONS
We observed ipsilateral MB atrophy in about one-quarter of patients with TLE and HS. The severity of subcortical limbic structure abnormalities was greater in patients without MB atrophy. These findings suggest that MB atrophy in TLE with HS is not rare, but it has little clinical significance.
PubMed: 36367061
DOI: 10.3988/jcn.2022.18.6.635 -
Molecules and Cells Feb 2021The bed nucleus of the stria terminalis (BNST)-a key part of the extended amygdala-has been implicated in the regulation of diverse behavioral states, ranging from... (Review)
Review
The bed nucleus of the stria terminalis (BNST)-a key part of the extended amygdala-has been implicated in the regulation of diverse behavioral states, ranging from anxiety and reward processing to feeding behavior. Among the host of distinct types of neurons within the BNST, recent investigations employing cell type- and projection-specific circuit dissection techniques (such as optogenetics, chemogenetics, deep-brain calcium imaging, and the genetic and viral methods for targeting specific types of cells) have highlighted the key roles of glutamatergic and GABAergic neurons and their axonal projections. As anticipated from their primary roles in excitatory and inhibitory neurotransmission, these studies established that the glutamatergic and GABAergic subpopulations of the BNST oppositely regulate diverse behavioral states. At the same time, these studies have also revealed unexpected functional specificity and heterogeneity within each subpopulation. In this Minireview, we introduce the body of studies that investigated the function of glutamatergic and GABAergic BNST neurons and their circuits. We also discuss unresolved questions and future directions for a more complete understanding of the cellular diversity and functional heterogeneity within the BNST.
Topics: Animals; Behavior; GABAergic Neurons; Glutamates; Humans; Models, Biological; Septal Nuclei
PubMed: 33594012
DOI: 10.14348/molcells.2021.0006 -
Cellular and Molecular Life Sciences :... Dec 2021Individuals of many species fight with conspecifics to gain access to or defend critical resources essential for survival and reproduction. Such intraspecific fighting... (Review)
Review
Individuals of many species fight with conspecifics to gain access to or defend critical resources essential for survival and reproduction. Such intraspecific fighting is evolutionarily selected for in a species-, sex-, and environment-dependent manner when the value of resources secured exceeds the cost of fighting. One such example is males fighting for chances to mate with females. Recent advances in new tools open up ways to dissect the detailed neural circuit mechanisms that govern intraspecific, particularly inter-male, aggression in the model organism Mus musculus (house mouse). By targeting and functional manipulating genetically defined populations of neurons and their projections, these studies reveal a core neural circuit that controls the display of reactive male-male attacks in mice, from sensory detection to decision making and action selection. Here, we summarize these critical results. We then describe various modulatory inputs that route into the core circuit to afford state-dependent and top-down modulation of inter-male attacks. While reviewing these exciting developments, we note that how the inter-male attack circuit converges or diverges with neural circuits that mediate other forms of social interactions remain not fully understood. Finally, we emphasize the importance of combining circuit, pharmacological, and genetic analysis when studying the neural control of aggression in the future.
Topics: Aggression; Animals; Decision Making; Estrogen Receptor alpha; Female; Instinct; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Nervous System; Nervous System Physiological Phenomena; Neurons; Sensation; Septal Nuclei; Sexual Behavior, Animal; Ventromedial Hypothalamic Nucleus
PubMed: 34687319
DOI: 10.1007/s00018-021-03956-x -
Human Brain Mapping Apr 2021Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the...
Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.
Topics: Adult; Central Amygdaloid Nucleus; Cerebral Cortex; Connectome; Female; Humans; Magnetic Resonance Imaging; Male; Multifactorial Inheritance; Nerve Net; Pedigree; Septal Nuclei; Thalamus
PubMed: 33314443
DOI: 10.1002/hbm.25314