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Neuropharmacology Mar 2023Stress coping strategies represent critical responses to environmental challenges, and active coping has been linked to stress resilience in humans. Understanding the...
Stress coping strategies represent critical responses to environmental challenges, and active coping has been linked to stress resilience in humans. Understanding the neuroadaptations that support these strategies may provide insights into adaptive and maladaptive stress responses. NMDA receptors (NMDARs) play key roles in neuroadaptation, and NMDARs have been specifically implicated in stress responsiveness. Constitutive knockout mice have been used to implicate the GluN2D NMDAR subunit in regulation of stress-sensitive and affective behavior, but the brain regions in which GluN2D expression changes drive these effects remain unknown. Here we report that following an acute restraint stressor, GluN2D subunit expression is specifically decreased in the bed nucleus of the stria terminalis (BNST), a key region involved in stress processing, in male but not female mice, with no differences found in the thalamus or ventral hippocampus in either sex. Rodents engage in active struggling events during restraint stress that may represent active coping strategies to stress. Thus, we assessed active coping bouts during acute and chronic restraint stress sessions in GluN2D knockout mice. During the first restraint session, GluN2D knockout mice exhibited a pronounced decrease in struggling bouts during restraint stress relative to wild-type littermates, consistent with a role of GluN2D in active coping responses to stress. Repeated, daily restraint sessions revealed a sex-specific role of GluN2D expression on certain aspects of active coping behaviors, with male GluN2D KO mice exhibiting a decrease in total coping bouts measured across five sessions. However, BNST-specific knockdown of GluN2D in male mice did not alter active coping bouts, suggesting either a multi-synaptic role of GluN2D and/or a developmental role of GluN2D in this behavior. Altogether, these data are consistent with a growing literature suggesting that exploration of GluN2D control of stress circuit actions may lead to a novel therapeutic target to consider for stress-related mood disorders.
Topics: Animals; Female; Male; Mice; Adaptation, Psychological; Brain; Hippocampus; Mice, Knockout; Receptors, N-Methyl-D-Aspartate; Restraint, Physical; Septal Nuclei; Stress, Psychological
PubMed: 36528117
DOI: 10.1016/j.neuropharm.2022.109377 -
Behavioural Brain Research Feb 2023Conditioned taste aversion (CTA) is established by pairing a taste solution as a conditioned stimulus (CS) with visceral malaise as an unconditioned stimulus (US). CTA...
Conditioned taste aversion (CTA) is established by pairing a taste solution as a conditioned stimulus (CS) with visceral malaise as an unconditioned stimulus (US). CTA decreases the taste palatability of a CS. The bed nucleus of the stria terminalis (BNST) receives taste inputs from the brainstem. However, the involvement of the BNST in CTA remains unclear. Thus, this study examined the effects of chemogenetic inhibition of the BNST neurons on CS intake after CTA acquisition. An adeno-associated virus was microinjected into the BNST of male C57/BL6 mice to induce the inhibitory designer receptor hM4Di. The mice received a pairing of 0.2% saccharin solution (CS) with 0.3 M lithium chloride (2% BW, intraperitoneal). After conditioning, the administration of clozapine-N-oxide (CNO, 1 mg/kg) significantly enhanced the suppression of CS intake on the retrieval of CTA compared with its intake following saline administration (p < 0.01). We further assessed the effect of BNST neuron inhibition on the intake of water and taste solutions (saccharin, sucralose, sodium chloride, monosodium glutamate, quinine hydrochloride, and citric acid) using naïve (not learned CTA) mice. CNO administration significantly decreased the intake of saccharin and sucralose (p < 0.05). Our results indicate that BNST neurons mediate sweet taste and regulate sweet intake, regardless of whether sweets should be ingested or rejected. BNST neurons may be inhibited in the retrieval of CTA, thereby suppressing CS intake.
Topics: Mice; Male; Animals; Taste; Conditioning, Psychological; Septal Nuclei; Saccharin; Avoidance Learning; Lithium Chloride
PubMed: 36509179
DOI: 10.1016/j.bbr.2022.114253 -
Boletin Medico Del Hospital Infantil de... 2022Congenital heart defects (CHD) are among the most frequent manifestations of 22q11.2 deletion syndrome. Although we found relatively few studies aimed at specifically...
BACKGROUND
Congenital heart defects (CHD) are among the most frequent manifestations of 22q11.2 deletion syndrome. Although we found relatively few studies aimed at specifically detecting 22q11.2 deletion in newborns (NB) with CHD, none of them has been performed in Mexico.
METHODS
We conducted a prospective hospital-based study from January 2017 to March 2021 in the Genetics and Pediatric Cardiology Services of the Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, Mexico). All consecutive NBs identified with any non-syndromic major CHD confirmed by echocardiography were eligible to participate. A total of 98 NBs were included, 51 males and 47 females. Fluorescence in situ hybridization (FISH) analysis was conducted to search for deletion of chromosome 22q11.2 in interphase nuclei of standard lymphocyte cultures.
RESULTS
We found eight patients (8.2%) with CHD and the 22q11.2 deletion, all of them with conotruncal defects, particularly of the truncus arteriosus (p = 0.013), tetralogy of Fallot (p = 0.024), and pulmonary atresia with ventricular septal defect (p = 0.031) subtypes. With de exception of one infant with hypocalcemia and another with hypocalcemia and thymic aplasia, the diagnosis of 22q11.2 deletion was not clinically suspected in the other patients.
CONCLUSIONS
Our results confirm the importance of excluding the presence of the 22q11.2 deletion in every NB with CHDs, particularly of the conotruncal subtype, even in the absence of other manifestations.
Topics: Humans; In Situ Hybridization, Fluorescence; Prospective Studies; Heart Defects, Congenital; Chromosomes; Mexico
PubMed: 36476817
DOI: 10.24875/BMHIM.22000078 -
Nature Jan 2023In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social...
In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NT) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NT neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NT neurons that occlude social reward processing.
Topics: Animals; Female; Male; Mice; Brain; Calcium; Mice, Inbred C57BL; Neural Pathways; Neurons; Neurotensin; Optogenetics; Psychological Trauma; Reward; Septal Nuclei; Social Behavior; Stress, Psychological
PubMed: 36450985
DOI: 10.1038/s41586-022-05484-5 -
Emerging Topics in Life Sciences Dec 2022Behavioural reactivity to potential threat is used to experimentally refine models of anxiety symptoms in rodents. We present a short review of the literature tying the... (Review)
Review
Behavioural reactivity to potential threat is used to experimentally refine models of anxiety symptoms in rodents. We present a short review of the literature tying the most commonly used tasks to model anxiety symptoms to functional recruitment of bed nucleus of the stria terminalis circuits (BNST). Using a review of studies that investigated the role of the BNST in anxiety-like behaviour in rodents, we flag the certain challenges for the field. These stem from inconsistent methods of reporting the neuroanatomical BNST subregions and the interpretations of specific behaviour across a wide variety of tasks as 'anxiety-like'. Finally, to assist in interpretation of the findings, we discuss the potential interactions between typically used 'anxiety' tasks of innate behaviour that are potentially modulated by the social and individual experience of the animal.
Topics: Animals; Rodentia; Septal Nuclei
PubMed: 36416376
DOI: 10.1042/ETLS20220002 -
Translational Psychiatry Nov 2022Serotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as...
Serotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD). Although in recent years, a considerable amount of evidence supports 5-HT2CRs facilitating effect on anxiety behavior, the involvement in learned fear responses and fear extinction is rather unexplored. Here, we used a 5-HT2CR knock-out mouse line (2CKO) to gain new insights into the involvement of 5-HT2CRs in the neuronal fear circuitry. Using a cued fear conditioning paradigm, our results revealed that global loss of 5-HT2CRs exclusively accelerates fear extinction, without affecting fear acquisition and fear expression. To investigate the neuronal substrates underlying the extinction enhancing effect, we mapped the immediate-early gene product cFos, a marker for neuronal activity, in the dorsal raphe nucleus (DRN), amygdala and bed nucleus of the stria terminalis (BNST). Surprisingly, besides extinction-associated changes, our results revealed alterations in neuronal activity even under basal home cage conditions in specific subregions of the DRN and the BNST in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in an extinction-supporting direction due to 5-HT2CR knock-out. Finally, the assessment of DRN-BNST connectivity using antero- and retrograde tracing techniques uncovered a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (DRC) to the anterodorsal portion of the BNST (BNSTad). This serotonergic DRC-BNSTad pathway showed increased neuronal activity in 2CKO mice. Thus, our results provide new insights for the fear extinction network by revealing a specific serotonergic DRC-BNSTad pathway underlying a 5-HT2CR-sensitive mechanism with high significance in the treatment of PTSD.
Topics: Mice; Animals; Fear; Septal Nuclei; Dorsal Raphe Nucleus; Extinction, Psychological; Receptor, Serotonin, 5-HT2C
PubMed: 36402746
DOI: 10.1038/s41398-022-02252-x -
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 -
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 -
Cell Reports Nov 2022Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying...
Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying stress responses are unclear. Here we demonstrate that photoactivation of Gad2+ projection from the anterior bed nucleus of the stria terminalis (aBNST) to the arcuate nucleus (ARC) induces anxiety-like behavior as well as acute hyperglycemia. Photoinhibition of the circuit is anxiolytic and blocks hyperglycemia induced by restraint stress. Pharmacogenetic inhibition of the ARC→raphe obscurus nucleus (ROb) and photoactivation of the aBNST→ARC circuits simultaneously leads to significant hypoglycemia and anxiety-like behavior. Pharmacogenetic inhibition of the ARC→nucleus of the solitary tract (NTS) whilst photoactivation of the aBNST→ARC circuit only induces hyperglycemia. Our results reveal that the aBNST→ARC→ROb circuit is recruited for the stress response of rapid glucose mobilization and the aBNST→ARC→NTS circuit for behavioral symptoms of stress response. This study identifies a possible general strategy for neurocircuitry structural organization dealing with multiple organs involved in responses, with potential therapeutic targets for emotion and energy metabolism disorders underlying psychiatric disorders.
Topics: Humans; Glucose; Septal Nuclei; Anxiety; Arcuate Nucleus of Hypothalamus; Hyperglycemia
PubMed: 36351404
DOI: 10.1016/j.celrep.2022.111586 -
Clinical Parkinsonism & Related... 2022Parkinson's disease (PD) mainly affects basal ganglia including septal nuclei. Septal nuclei have extensive cholinergic connections with thalamus and brain stem nuclei....
OBJECTIVE
Parkinson's disease (PD) mainly affects basal ganglia including septal nuclei. Septal nuclei have extensive cholinergic connections with thalamus and brain stem nuclei. We hypothesized that the degeneration of septal nuclei has an impact on dopaminergic (motor) and non-dopaminergic (cognitive) symptoms in PD.
METHOD
Clinical and MRI data of 80 patients with Parkinson's disease and 20 healthy controls (HC) with a structural magnetic resonance imaging (MRI) were selected from their first visit from PPMI database. Septal nuclei were manually segmented from T1W images according to previously established anatomical criteria. In addition, subcortical structures such as thalamus, amygdala, hippocampus, caudate, putamen, pallidum and accumbens were automatically segmented.
RESULTS
Volume of septal nuclei in the patients with PD was decreased in comparison with controls. These changes were independent of volume changes in other subcortical grey structure in PD. In addition, we found a correlation between motor components of unified Parkinson's disease rating scale (UPDRS) and volume of septal nuclei in PD. Other clinical measures such as olfactory test, upper extremity function (mobility) performance, total UPDRS, lower extremity function (mobility) performance, and cognitive function were significantly more in PD group than in control. No correction was found between cognitive function and volume of septal nuclei.
CONCLUSION
We concluded that septal nuclei is distinctly affected in PD and is strongly associated with motor impairment. This may be a modulatory effect of cholinergic system on dopaminergic and glutamergic system. It is suggested that volume of septal nuclei may be a useful biomarker in PD diagnosis and monitoring.
PubMed: 36338824
DOI: 10.1016/j.prdoa.2022.100171