-
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 -
Neuropharmacology May 2023Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are... (Review)
Review
Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the 'CRF exhaustion' in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders. This article is part of the Special Issue on "Fear, Anxiety and PTSD".
Topics: Animals; Corticotropin-Releasing Hormone; Fear; Neurons; Anxiety; Central Amygdaloid Nucleus; Adrenocorticotropic Hormone; Septal Nuclei
PubMed: 36775096
DOI: 10.1016/j.neuropharm.2023.109461 -
Brain Research Feb 2020The extended amygdala, including the Central nucleus of the Amygdala (CeA) and the Bed Nucleus of the Stria Terminalis (BNST), is a complex structure that plays a...
The extended amygdala, including the Central nucleus of the Amygdala (CeA) and the Bed Nucleus of the Stria Terminalis (BNST), is a complex structure that plays a pivotal role in emotional behavior. The CeA and the BNST are highly interconnected, being the amygdala traditionally more associated with fear and the BNST with anxiety. Yet, studies using excitotoxic lesions also show the involvement of the CeA in the development of stress-induced anxiety. Likewise, others have also highlighted the role of corticotropin-releasing factor (CRF), a neuropeptide highly expressed in CeA, as an anxiogenic factor and, consequently, important for in anxiety disorders. Here, we used an inducible RNAi lentiviral system to assess the effects of reducing CRF expression in CeA in the development of anxiety-like behavior in a model of Chronic Unpredictable Stress. In addition, we evaluated CRF RNAi-mediated alterations in the stress-triggered molecular signature in the BNST. Knockdown of CRF in the CeA decreased stress-induced anxiety levels. No differences were found in a fear-potentiated startle paradigm. Additionally, we observed that stress-induced alterations in the expression of CRF receptors within the BNST are attenuated by CRF knockdown in the CeA. These results emphasize the importance of the role that amygdalar CRF plays in the modulation of anxiety-like behavior and in the molecular signature of stress in the BNST.
Topics: Amygdala; Animals; Anxiety; Corticotropin-Releasing Hormone; Male; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Septal Nuclei; Stress, Psychological
PubMed: 31881185
DOI: 10.1016/j.brainres.2019.146622 -
Neuropsychopharmacology : Official... Jun 2023The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta (BNST)...
The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta (BNST) are an abundant but understudied subpopulation implicated in inhibiting feeding, but which have conflicting reports about their role in anxiety-like behaviors. We have previously shown that expression of PKCδ is dynamically regulated by stress and that BNST cells are recruited during bouts of active stress coping. Here, we first show that in vivo activation of this population is mildly aversive. This aversion was insensitive to prior restraint stress exposure. Further investigation revealed that unlike other BNST subpopulations, BNST cells do not exhibit increased cfos expression following restraint stress. Ex vivo current clamp recordings also indicate they are resistant to firing. To elucidate their afferent control, we next used rabies tracing with whole-brain imaging and channelrhodopsin-assisted circuit mapping, finding that BNST cells receive abundant input from affective, arousal, and sensory regions including the basolateral amygdala (BLA) paraventricular thalamus (PVT) and central amygdala PKCδ-expressing cells (CeA). Given these findings, we used in vivo optogenetics and fiber photometry to further examine BNST cells in the context of stress and anxiety-like behavior. We found that BNST cell activity is associated with increased anxiety-like behavior in the elevated plus maze, increases following footshock, and unlike other BNST subpopulations, does not desensitize to repeated stress exposure. Taken together, we propose a model in which BNST cells may serve as threat detectors, integrating exteroceptive and interoceptive information to inform stress coping behaviors.
Topics: Septal Nuclei; Anxiety; Central Amygdaloid Nucleus; Neurons; Affect
PubMed: 36941364
DOI: 10.1038/s41386-023-01569-5 -
Biological Psychiatry May 2024Social memory, the ability to recognize and remember individuals within a social group, is crucial for social interactions and relationships. Deficits in social memory... (Review)
Review
Social memory, the ability to recognize and remember individuals within a social group, is crucial for social interactions and relationships. Deficits in social memory have been linked to several neuropsychiatric and neurodegenerative disorders. The hippocampus, especially the circuit that links dorsal CA2 and ventral CA1 neurons, is considered a neural substrate for social memory formation. Recent studies have provided compelling evidence of extrahippocampal contributions to social memory. The septal nuclei, including the medial and lateral septum, make up a basal forebrain region that shares bidirectional neuronal connections with the hippocampus and has recently been identified as critical for social memory. The focus of our review is the neural circuit mechanisms that underlie social memory, with a special emphasis on the septum. We also discuss the social memory dysfunction associated with neuropsychiatric and neurodegenerative disorders.
PubMed: 38718881
DOI: 10.1016/j.biopsych.2024.04.018 -
The Journal of Neuroscience : the... Mar 2022Hippocampal theta oscillations (HTOs) during rapid eye movement (REM) sleep play an important role in mnemonic processes by coordinating hippocampal and cortical...
Hippocampal theta oscillations (HTOs) during rapid eye movement (REM) sleep play an important role in mnemonic processes by coordinating hippocampal and cortical activities. However, it is not fully understood how HTOs are modulated by subcortical regions, including the median raphe nucleus (MnR). The MnR is thought to suppress HTO through its serotonergic outputs. Here, our study on male mice revealed a more complex framework indicating roles of nonserotonergic MnR outputs in regulating HTO. We found that nonselective optogenetic activation of MnR neurons at theta frequency increased HTO amplitude. Granger causality analysis indicated that MnR theta oscillations during REM sleep influence HTO. By using three transgenic mouse lines, we found that MnR serotonergic neurons exhibited little or no theta-correlated activity during HTO. Instead, most MnR GABAergic neurons and Vglut3 neurons respectively increased and decreased activities during HTO and exhibited hippocampal theta phase-locked activities. Although MnR GABAergic neurons do not directly project to the hippocampus, they could modulate HTO through local Vglut3 and serotonergic neurons as we found that MnR GABAergic neurons monosynaptically targeted Vglut3 and serotonergic neurons. Additionally, pontine wave recorded from the MnR during REM sleep accompanied nonserotonergic activity increase and HTO acceleration. These results suggest that MnR nonserotonergic neurons modulate hippocampal theta activity during REM sleep, which regulates memory processes. The MnR is the major source of serotonergic inputs to multiple brain regions including the hippocampus and medial septal area. It has long been thought that those serotonergic outputs suppress HTOs. However, our results revealed that MnR serotoninergic neurons displayed little firing changes during HTO. Instead, MnR Vglut3 neurons were largely silent during HTO associated with REM sleep. Additionally, many MnR GABAergic neurons fired rhythmically phase-locked to HTO. These results indicate an important role of MnR nonserotonergic neurons in modulating HTO.
Topics: Animals; GABAergic Neurons; Hippocampus; Male; Mice; Raphe Nuclei; Septum of Brain; Serotonergic Neurons; Theta Rhythm
PubMed: 35064000
DOI: 10.1523/JNEUROSCI.1536-21.2022 -
Journal of Neurology Nov 2022We compared limbic structure volumes and graph theory parameters of the limbic covariance network between patients with transient global amnesia (TGA) and healthy...
BACKGROUND
We compared limbic structure volumes and graph theory parameters of the limbic covariance network between patients with transient global amnesia (TGA) and healthy controls, and between patients with single and recurrent TGA events.
METHODS
We retrospectively enrolled 122 patients with TGA (single event, n = 107; recurrent events, n = 15) and 50 healthy controls who underwent three-dimensional T1-weighted MRI imaging of the brain. Volumetric analysis of the subcortical limbic structures, including the hippocampus, amygdala, thalamus, mammillary body, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens, was performed. We examined the limbic covariance network using a graph theory.
RESULTS
Limbic structure volumes did not differ between patients with TGA and healthy controls, and between patients with a single event and those with recurrent events. However, the radius of the limbic covariance network was significantly greater in patients with TGA than in healthy controls (6.595 vs. 4.564, p = 0.040). Furthermore, the radius, diameter, eccentricity, and characteristics path length were greater (4.066 vs. 2.000, p = 0.009; 7.062 vs. 3.645, p = 0.029; 5.633 vs. 2.774, p = 0.013; 3.373 vs. 1.688, p = 0.004; respectively), whereas the average strength, global efficiency, local efficiency, mean clustering coefficient, transitivity, and small-worldness index were lower (5.595 vs. 10.831, p = 0.004; 0.350 vs. 0.642, p = 0.002; 0.531 vs. 1.724, p = 0.004; 0.304 vs. 0.624, p = 0.006; 0.456 vs. 0.935, p = 0.003; 0.913 vs. 0.993, p = 0.017; respectively), in patients with recurrent events than in those with a single event.
CONCLUSION
The limbic covariance network shows significant alterations in patients with TGA, as well as differences between patients with recurrent events and those with a single event. These findings suggest that changes in the limbic covariance network could be related to the pathogenesis of TGA.
Topics: Amnesia, Transient Global; Brain; Hippocampus; Humans; Magnetic Resonance Imaging; Retrospective Studies
PubMed: 35809126
DOI: 10.1007/s00415-022-11263-z