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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 -
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 -
Molecules (Basel, Switzerland) Jan 2018The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective... (Review)
Review
The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective antioxidant. An intact and functional pineal gland is necessary for preserving optimal human health. Unfortunately, this gland has the highest calcification rate among all organs and tissues of the human body. Pineal calcification jeopardizes melatonin's synthetic capacity and is associated with a variety of neuronal diseases. In the current review, we summarized the potential mechanisms of how this process may occur under pathological conditions or during aging. We hypothesized that pineal calcification is an active process and resembles in some respects of bone formation. The mesenchymal stem cells and melatonin participate in this process. Finally, we suggest that preservation of pineal health can be achieved by retarding its premature calcification or even rejuvenating the calcified gland.
Topics: Aging; Animals; Calcinosis; Humans; Melatonin; Pineal Gland; Rejuvenation
PubMed: 29385085
DOI: 10.3390/molecules23020301 -
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 -
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 -
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 -
Cell Reports Oct 2023Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in...
Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.
Topics: Mice; Animals; Depression; Neurons; Habenula; Chronic Pain; Thalamic Nuclei
PubMed: 37738124
DOI: 10.1016/j.celrep.2023.113170 -
Current Biology : CB Oct 2016The habenula is a tiny brain region the size of a pea in humans. This region is highly conserved across vertebrates and has been traditionally overlooked by...
The habenula is a tiny brain region the size of a pea in humans. This region is highly conserved across vertebrates and has been traditionally overlooked by neuroscientists. The name habenula is derived from the Latin word habena, meaning "little rein", because of its elongated shape. Originally its function was thought to be related to the regulation of the nearby pineal gland (which Rene Descartes described as the "principal seat of the soul"). More recent evidence, however, demonstrates that the habenula acts as a critical neuroanatomical hub that connects and regulates brain regions important for divergent motivational states and cognition. In this Primer, we will discuss the recent and converging evidence that points to the habenula as a key brain region for motivation and decision-making.
Topics: Animals; Decision Making; Habenula; Humans; Motivation; Transcriptome
PubMed: 27728786
DOI: 10.1016/j.cub.2016.08.051 -
Neuron Apr 2017The brains of humans and other animals are asymmetrically organized, but we still know little about the ontogenetic and neural fundaments of lateralizations. Here, we... (Review)
Review
The brains of humans and other animals are asymmetrically organized, but we still know little about the ontogenetic and neural fundaments of lateralizations. Here, we review the current state of understanding about the role of genetic and non-genetic factors for the development of neural and behavioral asymmetries in vertebrates. At the genetic level, the Nodal signaling cascade is of central importance, but several other genetic pathways have been discovered to also shape the lateralized embryonic brain. Studies in humans identified several relevant genes with mostly small effect sizes but also highlight the extreme importance of non-genetic factors for asymmetry development. This is also visible in visual asymmetry in birds, in which genes only affect embryonic body position, while the resulting left-right difference of visual stimulation shapes visual pathways in a lateralized way. These and further studies in zebrafish and humans highlight that the many routes from genes to asymmetries of function run through left-right differences of neural pathways. They constitute the lateralized blueprints of our perception, cognition, and action.
Topics: Animals; Functional Laterality; Habenula; Humans; Neural Pathways; Photic Stimulation; Visual Pathways; Visual Perception
PubMed: 28426959
DOI: 10.1016/j.neuron.2017.02.045 -
Nature Neuroscience Jul 2023Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided...
Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles and projection patterns. We found that genetically defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors, such as estrogen receptor 1-expressing (Esr1) LHA-LHb neurons induce aversion, whereas neuropeptide Y-expressing (Npy) LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1 LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive signals in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1 LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types and provide evidence for the role of Esr1 neurons in aversion and sexually dimorphic stress sensitivity.
Topics: Female; Mice; Animals; Habenula; Hypothalamus; Hypothalamic Area, Lateral; Neurons; Affect; Neural Pathways
PubMed: 37349481
DOI: 10.1038/s41593-023-01367-8