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NeuroImage Jun 2022Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural...
Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.
Topics: Animals; Hippocampus; Humans; Hypothalamo-Hypophyseal System; Macaca; Pituitary-Adrenal System; Septal Nuclei
PubMed: 35304264
DOI: 10.1016/j.neuroimage.2022.119096 -
The Journal of Comparative Neurology Sep 2022The macroscale neuronal connections of the lateral preoptic area (LPO) and the caudally adjacent lateral hypothalamic area anterior region (LHAa) were investigated in...
The macroscale neuronal connections of the lateral preoptic area (LPO) and the caudally adjacent lateral hypothalamic area anterior region (LHAa) were investigated in mice by anterograde and retrograde axonal tracing. Both hypothalamic regions are highly and diversely connected, with connections to >200 gray matter regions spanning the forebrain, midbrain, and rhombicbrain. Intrahypothalamic connections predominate, followed by connections with the cerebral cortex and cerebral nuclei. A similar overall pattern of LPO and LHAa connections contrasts with substantial differences between their input and output connections. Strongest connections include outputs to the lateral habenula, medial septal and diagonal band nuclei, and inputs from rostral and caudal lateral septal nuclei; however, numerous additional robust connections were also observed. The results are discussed in relation to a current model for the mammalian forebrain network that associates LPO and LHAa with a range of functional roles, including reward prediction, innate survival behaviors (including integrated somatomotor and physiological control), and affect. The present data suggest a broad and intricate role for LPO and LHAa in behavioral control, similar in that regard to previously investigated LHA regions, contributing to the finely tuned sensory-motor integration that is necessary for behavioral guidance supporting survival and reproduction.
Topics: Animals; Cerebral Cortex; Hypothalamic Area, Lateral; Hypothalamus; Mammals; Mice; Preoptic Area; Septal Nuclei
PubMed: 35579973
DOI: 10.1002/cne.25331 -
Reviews in the Neurosciences Jul 2023Grid cells, in entorhinal cortex (EC) and related structures, signal animal location relative to hexagonal tilings of 2D space. A number of modeling papers have... (Review)
Review
Grid cells, in entorhinal cortex (EC) and related structures, signal animal location relative to hexagonal tilings of 2D space. A number of modeling papers have addressed the question of how grid firing behaviors emerge using (for example) ideas borrowed from dynamical systems (attractors) or from coupled oscillator theory. Here we use a different approach: instead of asking how grid behavior emerges, we take as a given the experimentally observed intracellular potentials of superficial medial EC neurons during grid firing. Employing a detailed neural circuit model modified from a lateral EC model, we then ask how the circuit responds when group of medial EC principal neurons exhibit such potentials, simultaneously with a simulated theta frequency input from the septal nuclei. The model predicts the emergence of robust theta-modulated gamma/beta oscillations, suggestive of oscillations observed in an medial EC experimental model (Cunningham, M.O., Pervouchine, D.D., Racca, C., Kopell, N.J., Davies, C.H., Jones, R.S.G., Traub, R.D., and Whittington, M.A. (2006). Neuronal metabolism governs cortical network response state. Proc. Natl. Acad. Sci. U S A 103: 5597-5601). Such oscillations result because feedback interneurons tightly synchronize with each other - despite the varying phases of the grid cells - and generate a robust inhibition-based rhythm. The lack of spatial specificity of the model interneurons is consistent with the lack of spatial periodicity in parvalbumin interneurons observed by Buetfering, C., Allen, K., and Monyer, H. (2014). Parvalbumin interneurons provide grid cell-driven recurrent inhibition in the medial entorhinal cortex. Nat. Neurosci. 17: 710-718. If EC gamma rhythms arise during exploration as our model predicts, there could be implications for interpreting disrupted spatial behavior and gamma oscillations in animal models of Alzheimer's disease and schizophrenia. Noting that experimental intracellular grid cell potentials closely resemble cortical Up states and Down states, during which fast oscillations also occur during Up states, we propose that the co-occurrence of slow principal cell depolarizations and fast network oscillations is a general property of the telencephalon, in both waking and sleep states.
Topics: Animals; Humans; Grid Cells; Action Potentials; Gamma Rhythm; Parvalbumins; Neurons; Entorhinal Cortex
PubMed: 36326795
DOI: 10.1515/revneuro-2022-0107 -
Neuropeptides Feb 2023Galanin (GAL) is a 29 amino acid peptide present in the central nervous system (CNS) as well as peripheral tissues in vertebrates. However, the brain distribution...
Galanin (GAL) is a 29 amino acid peptide present in the central nervous system (CNS) as well as peripheral tissues in vertebrates. However, the brain distribution pattern of GAL is understudied in reptiles. The aim of this study was to determine the organization of galaninergic neuronal system in the brain of the gecko Hemidactylus frenatus, a tropical and sub-tropical lizard, using rabbit anti-galanin antibody. In the telencephalon, GAL-ir perikarya and fibres were found in the lateral septal nucleus, but only GAL-ir fibres were observed in the striatum, nucleus accumbens, anterior commissure, nucleus centralis amygdalae, dorsal and medial septal nuclei, nucleus of the diagonal band of Broca and in the optic chiasma. In the preoptic region, a cluster of GAL-ir cells and fibres was observed in the periventricular preoptic area and lateral preoptic area. GAL-ir perikarya and fibres were observed in hypothalamic areas such as the supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, periventricular nucleus of the hypothalamus, infundibular recess nucleus and in the median eminence, whereas GAL-ir fibres were present in the pars distalis of the pituitary gland. In the thalamus, GAL-ir fibres were observed in the dorsomedial, dorsolateral, and medial thalamic nuclei. GAL-ir fibres were also detected in mesencephalic areas such as the optic tectum, torus semicircularis, ventral tegmental area and substantia nigra, brain stem as well as the spinal cord. The organization of GAL-ir cells and fibres throughout the gecko brain suggests several neuroendocrine, neuromodulatory and behavioural functions for GAL in lizards. The study provides new insights into the evolutionarily conserved nature of GAL peptide in squamate reptiles and forms a valuable basis for future comparative studies.
Topics: Animals; Rabbits; Brain; Mesencephalon; Central Nervous System; Peptides; Lizards
PubMed: 36459764
DOI: 10.1016/j.npep.2022.102310 -
Frontiers in Neural Circuits 2023The vast majority of studies on hippocampal rhythms have been conducted on animals or humans in situations where their attention was focused on external stimuli or... (Review)
Review
The vast majority of studies on hippocampal rhythms have been conducted on animals or humans in situations where their attention was focused on external stimuli or solving cognitive tasks. These studies formed the basis for the idea that rhythmical activity coordinates the work of neurons during information processing. However, at rest, when attention is not directed to external stimuli, brain rhythms do not disappear, although the parameters of oscillatory activity change. What is the functional load of rhythmical activity at rest? Hippocampal oscillatory activity during rest is called the non-theta state, as opposed to the theta state, a characteristic activity during active behavior. We dedicate our review to discussing the present state of the art in the research of the non-theta state. The key provisions of the review are as follows: (1) the non-theta state has its own characteristics of oscillatory and neuronal activity; (2) hippocampal non-theta state is possibly caused and maintained by change of rhythmicity of medial septal input under the influence of raphe nuclei; (3) there is no consensus in the literature about cognitive functions of the non-theta-non-ripple state; and (4) the antagonistic relationship between theta and delta rhythms observed in rodents is not always observed in humans. Most attention is paid to the non-theta-non-ripple state, since this aspect of hippocampal activity has not been investigated properly and discussed in reviews.
Topics: Animals; Humans; Theta Rhythm; Hippocampus; Neurons; Attention; Cognition
PubMed: 36960401
DOI: 10.3389/fncir.2023.1134705 -
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