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Neuropharmacology Oct 2021Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral... (Review)
Review
Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral assays. This is reflected in the heterogeneous neuronal populations within the PBN to the extended amygdala (EA) circuits which encompass the bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) circuitry, as they differentially modulate aspects of behavior in response to diverse threat-like contexts necessary for survival. Here we review how the PBN→CeA and PBN→BNST pathways differentially modulate fear-like behavior, innate and conditioned, through unique changes in neurotransmission in response to stress-inducing contexts. Furthermore, we hypothesize how in specific instances the PBN→CeA and PBN→BNST circuits are redundant and in part intertwined with their respective reciprocal projections. By deconstructing the interoceptive and exteroceptive components of affect- and stress related behavioral paradigms, evidence suggests that the PBN→CeA circuit modulates innate response to physical stimuli and fear conditioning. Conversely, the PBN→BNST circuit modulates distress-like stress in unpredictable contexts. Thereby, the PBN provides a pathway for alarming interoceptive and exteroceptive stimuli to be processed and relayed to the EA to induce stress-relevant affect. Additionally, we provide a framework for future studies to detail the cell-type specific intricacies of PBN→EA circuits in mediating behavioral responses to threats, and the relevance of the PBN in drug-use as it relates to threat and negative reinforcement. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.
Topics: Affect; Amygdala; Animals; Fear; Humans; Parabrachial Nucleus; Septal Nuclei; Stress, Psychological
PubMed: 34461068
DOI: 10.1016/j.neuropharm.2021.108757 -
Behavioural Brain Research Jan 2021Accurate discrimination between safe and dangerous stimuli is essential for survival. Prior research has begun to uncover the neural structures that are necessary for...
Accurate discrimination between safe and dangerous stimuli is essential for survival. Prior research has begun to uncover the neural structures that are necessary for learning this discrimination, but exploration of brain regions involved in this learning process has been mostly limited to males. Recent findings show sex differences in discrimination learning, with reduced fear expression to safe cues in females compared to males. Here, we used male and female Sprague Dawley rats to explore neural activation, as measured by Fos expression, in fear and safety learning related brain regions. Neural activation after fear discrimination (Discrimination) was compared between males and females, as well as with fear conditioned (Fear Only) and stimulus presented (Control) conditions. Correlations of discrimination ability and neural activation were also calculated. We uncovered a correlation between central amygdala (CeA) activation and discrimination abilities in males and females. Anterior medial bed nucleus of the stria terminalis (BNST) was the only region where sex differences in Fos counts were observed in the Discrimination condition, and the only region where neural activation significantly differed between Fear Only and Discrimination conditions. Together, these findings indicate the importance of fear expression circuitry in mediating discrimination responses and generate important questions for future investigation.
Topics: Animals; Behavior, Animal; Central Amygdaloid Nucleus; Conditioning, Classical; Discrimination Learning; Fear; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Septal Nuclei; Sex Characteristics
PubMed: 32871228
DOI: 10.1016/j.bbr.2020.112884 -
Stress (Amsterdam, Netherlands) 2015For centuries philosophical and clinical studies have emphasized a fundamental dichotomy between emotion and cognition, as, for instance, between behavioral/emotional... (Review)
Review
For centuries philosophical and clinical studies have emphasized a fundamental dichotomy between emotion and cognition, as, for instance, between behavioral/emotional memory and explicit/representative memory. However, the last few decades cognitive neuroscience have highlighted data indicating that emotion and cognition, as well as their underlying neural networks, are in fact in close interaction. First, it turns out that emotion can serve cognition, as exemplified by its critical contribution to decision-making or to the enhancement of episodic memory. Second, it is also observed that reciprocally cognitive processes as reasoning, conscious appraisal or explicit representation of events can modulate emotional responses, like promoting or reducing fear. Third, neurobiological data indicate that reciprocal amygdalar-hippocampal influences underlie such mutual regulation of emotion and cognition. While supporting this view, the present review discusses experimental data, obtained in rodents, indicating that the hippocampal and amygdalar systems not only regulate each other and their functional outcomes, but also qualify specific emotional memory representations through specific activations and interactions. Specifically, we review consistent behavioral, electrophysiological, pharmacological, biochemical and imaging data unveiling a direct contribution of both the amygdala and hippocampal-septal system to the identification of the predictor of a threat in different situations of fear conditioning. Our suggestion is that these two brain systems and their interplay determine the selection of relevant emotional stimuli, thereby contributing to the adaptive value of emotional memory. Hence, beyond the mutual quantitative regulation of these two brain systems described so far, we develop the idea that different activations of the hippocampus and amygdala, leading to specific configurations of neural activity, qualitatively impact the formation of emotional memory representations, thereby producing either adaptive or maladaptive fear memories.
Topics: Adaptation, Psychological; Amygdala; Animals; Brain; Cognition; Conditioning, Psychological; Decision Making; Emotions; Fear; Hippocampus; Humans; Memory; Septal Nuclei
PubMed: 26260664
DOI: 10.3109/10253890.2015.1067676 -
The European Journal of Neuroscience Oct 2018Anatomical differences between the medial and lateral septum have associated these nuclei with dissimilar functional roles and behaviours. While the medial septum has... (Review)
Review
Anatomical differences between the medial and lateral septum have associated these nuclei with dissimilar functional roles and behaviours. While the medial septum has been implicated, predominantly, in theta rhythm generation along the septo-hippocampal axis, the lateral septum has mainly been investigated in the context of septo-hypothalamic dialogue. Recent advances suggest that medial and lateral septum are more closely functionally related than previously appreciated. Here, we explore the hypothesis that the medial septum mediates ascending septo-hippocampal theta propagation, while the lateral septum processes a descending hippocampo-septal and septo-hypothalamic reinforcement signal that mediates navigation during motivated behaviour. The generation and propagation of theta rhythm are critical for the initiation of exploratory behaviour. Indeed, theta signal processing of medial and lateral septum nuclei may well be involved in the integration of spatial, rewarding and locomotor signals across different brain networks. We review here the structural features, anatomical connectivity and functional properties of the medial and lateral septum. We discuss the heterogeneous anatomy of the lateral septum, which is composed of diverse subregions with distinct ascending and descending projections, and we relate the physiological characteristics of septal nuclei to their functional relationships with the hippocampal formation, the hypothalamus and the brainstem reticular formation during motivated spatial navigation.
Topics: Animals; Brain Waves; Hippocampus; Humans; Limbic System; Neural Pathways; Septal Nuclei; Septum of Brain; Theta Rhythm
PubMed: 29044802
DOI: 10.1111/ejn.13746 -
CNS Spectrums Feb 2022In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety... (Review)
Review
In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety and antidepressant properties, that engage nasal chemosensory receptors. We hypothesize that afferent signals triggered by activation of these peripheral receptors could reach subgroups of olfactory bulb neurons broadcasting information to gamma-aminobutyric acid (GABAergic) and corticotropin-releasing hormone (CRH) neurons in the limbic amygdala. We propose that chemosensory inputs triggered by pherines project to centrolateral (CeL) and centromedial (CeM) amygdala neurons, with downstream effects mediating behavioral actions. Anxiolytic pherines could activate the forward inhibitory GABAergic neurons that facilitate the release of neuropeptide S (NPS) in the locus coeruleus (LC) and GABA in the bed nucleus of the stria terminalis (BNST) and inhibit catecholamine release in the LC and ventral tegmental area (VTA) leading to rapid anxiolytic effect. Alternatively, antidepressant pherines could facilitate the CRH and GABAergic neurons that inhibit the release of NPS from the LC, increase glutamate release from the BNST, and increase norepinephrine (NE), dopamine (DA), and serotonin release from the LC, VTA, and raphe nucleus, respectively. Activation of these neural circuits leads to rapid antidepressant effect. The information provided is consistent with this model, but it should be noted that some steps on these pathways have not been demonstrated conclusively in the human brain.
Topics: Anti-Anxiety Agents; Antidepressive Agents; Corticotropin-Releasing Hormone; Humans; Septal Nuclei; Ventral Tegmental Area
PubMed: 33092667
DOI: 10.1017/S109285292000190X -
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 -
NeuroImage Apr 2020The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use...
The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.
Topics: Adolescent; Adult; Cerebral Cortex; Diffusion Tensor Imaging; Echo-Planar Imaging; Female; Humans; Male; Middle Aged; Nerve Net; Septal Nuclei; Sex Characteristics; Sex Factors; Young Adult
PubMed: 31954845
DOI: 10.1016/j.neuroimage.2020.116555 -
Brain Research Oct 2023The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei...
The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.
Topics: Adult; Animals; Humans; Septal Nuclei; Brain; Diffusion Tensor Imaging; Hypothalamus; Occipital Lobe
PubMed: 37488033
DOI: 10.1016/j.brainres.2023.148510 -
Current Opinion in Pharmacology Jun 2021Oxytocin regulates a variety of centrally-mediated functions, ranging from socio-sexual behavior, maternal care, and affiliation to fear, stress, anxiety. In the past... (Review)
Review
Oxytocin regulates a variety of centrally-mediated functions, ranging from socio-sexual behavior, maternal care, and affiliation to fear, stress, anxiety. In the past years, both clinical and preclinical studies characterized oxytocin for its modulatory role on reward-related neural substrates mainly involving the interplay with the mesolimbic and mesocortical dopaminergic pathways. This suggests a role of this nonapeptide on the neurobiology of addiction raising the possibility of its therapeutic use. Although far from a precise knowledge of the underlying mechanisms, the putative role of the bed nucleus of the stria terminalis as a key structure where oxytocin may rebalance altered neurochemical processes and neuroplasticity involved in dependence and relapse has been highlighted. This view opens new opportunities to address the health problems related to drug misuse.
Topics: Anxiety; Humans; Neuronal Plasticity; Oxytocin; Septal Nuclei
PubMed: 33845377
DOI: 10.1016/j.coph.2021.03.002 -
The European Journal of Neuroscience May 2022The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic, neuropeptide-rich node of the extended amygdala that has been implicated in responses to stress,... (Review)
Review
The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic, neuropeptide-rich node of the extended amygdala that has been implicated in responses to stress, drugs of abuse, and natural rewards. Its function is dysregulated in neuropsychiatric disorders that are characterized by stress- or drug-induced alterations in mood, arousal, motivation, and social behavior. However, compared to the BNST's role in mood, arousal, and motivation, its role in social behavior has remained relatively understudied. Moreover, the precise cell types and circuits underlying the BNST's role in social behavior have only recently begun to be explored using modern neuroscience techniques. Here, we systematically review the existing literature investigating the neurobiological substrates within the BNST that contribute to the coordination of various sex-dependent and sex-independent social behavioral repertoires, focusing largely on pharmacological and circuit-based behavioral studies in rodents. We suggest that the BNST coordinates social behavior by promoting appropriate assessment of social contexts to select relevant behavioral outputs and that disruption of socially relevant BNST systems by stress and drugs of abuse may be an important factor in the development of social dysfunction in neuropsychiatric disorders.
Topics: Amygdala; Neuropeptides; Septal Nuclei; Social Behavior
PubMed: 33006806
DOI: 10.1111/ejn.14991