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Current Opinion in Neurobiology Feb 2018Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and... (Review)
Review
Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and discomfort without a clear cause. Depression has been suggested to be the result of maladaptive changes in specific brain circuits. Recently, the lateral habenula (LHb) has emerged as a key brain region in the pathophysiology of depression. Increasing evidence from rodent, non-human primate and human studies indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Revealing the molecular, cellular and circuit properties of the LHb will help explain how abnormalities in LHb activity are linked to depressive disorders, and shed light on developing novel strategies for depression treatment.
Topics: Animals; Depressive Disorder; Disease Models, Animal; Habenula; Humans; Nerve Net; Neurons
PubMed: 29175713
DOI: 10.1016/j.conb.2017.10.024 -
Neuron Apr 2022Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given...
Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.
Topics: Animals; Depression; Habenula; Hypothalamic Area, Lateral; Hypothalamus; Mice; Synapses
PubMed: 35114101
DOI: 10.1016/j.neuron.2022.01.011 -
Cell Sep 2022Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential...
Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH cells and Tac1 cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1 cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems.
Topics: Habenula; Population Dynamics; Reward
PubMed: 36113428
DOI: 10.1016/j.cell.2022.08.019 -
Neuron Jun 2020The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this,...
The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial habenular (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naive mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, differentially engaged by aversive stimuli, and had distinct electrophysiological properties. Cell types identified in mice also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well-conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenular cell types and provide a critical resource for future studies.
Topics: Animals; Astrocytes; Endothelial Cells; Ependymoglial Cells; Gene Expression Profiling; Gene Ontology; Habenula; Mice; Microglia; Neuroglia; Neurons; Oligodendroglia; RNA-Seq; Single-Cell Analysis; Zebrafish
PubMed: 32272058
DOI: 10.1016/j.neuron.2020.03.011 -
Nature Oct 2023Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant...
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects. Although the elimination half-life of ketamine is only 13 min in mice, its antidepressant activities can last for at least 24 h. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.
Topics: Animals; Mice; Antidepressive Agents; Depression; Habenula; Half-Life; Ketamine; Neurons; Receptors, N-Methyl-D-Aspartate; Time Factors; Protein Binding
PubMed: 37853123
DOI: 10.1038/s41586-023-06624-1 -
Neuron Dec 2021The lateral hypothalamic area (LHA) regulates feeding- and reward-related behavior, but because of its molecular and anatomical heterogeneity, the functions of defined...
The lateral hypothalamic area (LHA) regulates feeding- and reward-related behavior, but because of its molecular and anatomical heterogeneity, the functions of defined neuronal populations are largely unclear. Glutamatergic neurons within the LHA (LHA) negatively regulate feeding and appetitive behavior. However, this population comprises transcriptionally distinct and functionally diverse neurons that project to diverse brain regions, including the lateral habenula (LHb) and ventral tegmental area (VTA). To resolve the function of distinct LHA populations, we systematically compared projections to the LHb and VTA using viral tracing, single-cell sequencing, electrophysiology, and in vivo calcium imaging. LHA neurons projecting to the LHb or VTA are anatomically, transcriptionally, electrophysiologically, and functionally distinct. While both populations encode appetitive and aversive stimuli, LHb projecting neurons are especially sensitive to satiety state and feeding hormones. These data illuminate the functional heterogeneity of LHA neurons, suggesting that reward and aversion are differentially processed in divergent efferent pathways.
Topics: Glutamic Acid; Habenula; Hypothalamic Area, Lateral; Neural Pathways; Neurons; Ventral Tegmental Area
PubMed: 34624220
DOI: 10.1016/j.neuron.2021.09.020 -
Science (New York, N.Y.) Aug 2013The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes...
The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent protein kinase type II (βCaMΚΙΙ) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing β-, but not α-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of βCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.
Topics: Animals; Antidepressive Agents; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Depressive Disorder, Major; Disease Models, Animal; Gene Knockdown Techniques; Habenula; Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Promoter Regions, Genetic; Proteomics; Rats; Rats, Sprague-Dawley
PubMed: 23990563
DOI: 10.1126/science.1240729 -
Advanced Science (Weinheim,... Aug 2022Postoperative cognitive dysfunction (POCD) is common and is associated with poor outcome. Neural circuit involvement in POCD is unknown. Lateral habenula (LHb) that...
Postoperative cognitive dysfunction (POCD) is common and is associated with poor outcome. Neural circuit involvement in POCD is unknown. Lateral habenula (LHb) that regulates coping and depression-like behaviors after aversive stimuli is activated by surgery in the previous study. Here, surgery activated LHb and ventral tegmental area (VTA) are presented. VTA is known to receive projections from LHb and project to the prefrontal cortex and hippocampus. Direct chemogenetic inhibition of LHb or damaging LHb attenuates surgery-induced learning and memory impairment, N-methyl-d-aspartate (NMDA) receptor activation, endoplasmic reticulum stress, inflammatory responses and cell injury in the VTA, and activation of rostromedial tegmental nucleus, an intermediate station to connect LHb with VTA. LHb inhibition preserves dendritic spine density in the prefrontal cortex and hippocampus. Retrograde inhibition of LHb via its projections to VTA attenuated surgery-induced learning and memory dysfunction is observed. Retrograde activation of LHb induced learning and memory dysfunction is observed. Inhibition of NMDA receptors, dopamine synthesis, and endoplasmic reticulum stress in the VTA reduced surgery-induced learning and memory impairment, inflammatory responses, and cell injury are observed. These results suggest that surgery activates the LHb-VTA neural circuit, which contributes to POCD and neuropathological changes in the brain. These novel findings represent initial evidence for neural circuit involvement in surgery effects.
Topics: Animals; Habenula; Mice; N-Methylaspartate; Neural Pathways; Postoperative Cognitive Complications; Ventral Tegmental Area
PubMed: 35616407
DOI: 10.1002/advs.202202228 -
Neuron Apr 2023Parental behaviors secure the well-being of newborns and concomitantly limit negative affective states in adults, which emerge when coping with neonatal distress becomes...
Parental behaviors secure the well-being of newborns and concomitantly limit negative affective states in adults, which emerge when coping with neonatal distress becomes challenging. Whether negative-affect-related neuronal circuits orchestrate parental actions is unknown. Here, we identify parental signatures in lateral habenula neurons receiving bed nucleus of stria terminalis innervation (LHb). We find that LHb neurons of virgin female mice increase their activity following pup distress vocalization and are necessary for pup-call-driven aversive behaviors. LHb activity rises during pup retrieval, a behavior worsened by LHb inactivation. Intersectional cell identification and transcriptional profiling associate LHb cells to parenting and outline a gene expression in female virgins similar to that in mothers but different from that in non-parental virgin male mice. Finally, tracking and manipulating LHb cell activity demonstrates their specificity for encoding negative affect and pup retrieval. Thus, a negative affect neural circuit processes newborn distress signals and may limit them by guiding female parenting.
Topics: Mice; Animals; Male; Female; Neurons; Avoidance Learning; Affect; Habenula
PubMed: 36731469
DOI: 10.1016/j.neuron.2023.01.003 -
Neuron Apr 2019Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not...
Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.
Topics: Animals; Behavior, Animal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Depression; Depressive Disorder; Disease Models, Animal; GABAergic Neurons; Geniculate Bodies; Habenula; Male; Neural Inhibition; Neurons; Phototherapy; Retina; Retinal Ganglion Cells; Rod Opsins; Stress, Psychological; Thalamus; Visual Pathways
PubMed: 30795900
DOI: 10.1016/j.neuron.2019.01.037