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ELife Mar 2023The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits...
The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remain unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes in the mouse brain. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of the thalamus yielded novel insight into the PVT's connectivity with the cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.
Topics: Rats; Mice; Animals; Paraventricular Hypothalamic Nucleus; In Situ Hybridization, Fluorescence; Rats, Sprague-Dawley; Neural Pathways; Thalamus; Midline Thalamic Nuclei
PubMed: 36867023
DOI: 10.7554/eLife.81818 -
Nature Jan 2021Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural...
Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs), respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV and USV mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV and USV mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOA neurons) robustly promoted USV mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvl neurons) promoted USV mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOA and VMHvl neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.
Topics: Aggression; Animals; Copulation; Estrogen Receptor alpha; Female; Homosexuality, Male; Hypothalamus; Male; Mice; Optogenetics; Preoptic Area; Sexual Behavior, Animal; Vesicular Inhibitory Amino Acid Transport Proteins
PubMed: 33268894
DOI: 10.1038/s41586-020-2995-0 -
Nature Aug 2022Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus. The bed nucleus of the stria...
Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus. The bed nucleus of the stria terminalis (BNSTpr) is a node that receives input encoding sex-specific olfactory cues from the medial amygdala, and which in turn projects to hypothalamic nuclei that control mating (medial preoptic area (MPOA)) and aggression (ventromedial hypothalamus, ventrolateral subdivision (VMHvl)), respectively. Previous studies have demonstrated that male aromatase-positive BNSTpr neurons are required for mounting and attack, and may identify conspecific sex according to their overall level of activity. However, neural representations in BNSTpr, their function and their transformations in the hypothalamus have not been characterized. Here we performed calcium imaging of male BNSTpr neurons during social behaviours. We identify distinct populations of female- versus male-tuned neurons in BNSTpr, with the former outnumbering the latter by around two to one, similar to the medial amygdala and MPOA but opposite to VMHvl, in which male-tuned neurons predominate. Chemogenetic silencing of BNSTpr neurons while imaging MPOA or VMHvl neurons in behaving animals showed, unexpectedly, that the male-dominant sex-tuning bias in VMHvl was inverted to female-dominant whereas a switch from sniff- to mount-selective neurons during mating was attenuated in MPOA. Our data also indicate that BNSTpr neurons are not essential for conspecific sex identification. Rather, they control the transition from appetitive to consummatory phases of male social behaviours by shaping sex- and behaviour-specific neural representations in the hypothalamus.
Topics: Aggression; Amygdala; Animals; Calcium; Female; Hypothalamus; Male; Neurons; Preoptic Area; Sex Characteristics; Sexual Behavior, Animal; Social Behavior
PubMed: 35922505
DOI: 10.1038/s41586-022-05057-6 -
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 -
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 -
Cell Stem Cell May 2023Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack...
Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain.
Topics: Humans; Thalamic Nuclei; Thalamus; Neurons; Organoids
PubMed: 37019105
DOI: 10.1016/j.stem.2023.03.007 -
Cell Research Oct 2023Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons...
Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus define these neurons as spino-cortical recipient neurons (SCRNs). Morphological studies revealed that the branches from spinal ascending axons formed a kind of disciform structure with the descending axons from SCRNs in the basilar pontine nucleus (BPN). Electron microscopy and calcium imaging further confirmed that the axon terminals from spinal ascending neurons and SCRNs made functional synaptic contacts in the BPN, linking the ascending sensory pathway to the descending motor control pathway. Furthermore, behavioral tests indicated that the spino-cortical connection in the BPN was involved in nociceptive responses. In vivo calcium imaging showed that SCRNs responded to peripheral noxious stimuli faster than neighboring layer 4 cortical neurons in awake mice. Manipulating activities of SCRNs could modulate nociceptive behaviors. Therefore, this direct spino-cortical circuit represents a noncanonical pathway, allowing a fast sensory-motor transition of the brain in response to noxious stimuli.
Topics: Mice; Animals; Nociception; Calcium; Thalamus; Neurons
PubMed: 37311832
DOI: 10.1038/s41422-023-00832-0 -
Neuron Feb 2023Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were...
Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (T). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated T. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing T from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing T.
Topics: Mice; Animals; Body Temperature; Body Temperature Regulation; Hypothalamus; Preoptic Area; GABAergic Neurons; Mammals
PubMed: 36476978
DOI: 10.1016/j.neuron.2022.11.008 -
Cell Jan 2023The hypothalamus regulates innate social behaviors, including mating and aggression. These behaviors can be evoked by optogenetic stimulation of specific neuronal...
The hypothalamus regulates innate social behaviors, including mating and aggression. These behaviors can be evoked by optogenetic stimulation of specific neuronal subpopulations within MPOA and VMHvl, respectively. Here, we perform dynamical systems modeling of population neuronal activity in these nuclei during social behaviors. In VMHvl, unsupervised analysis identified a dominant dimension of neural activity with a large time constant (>50 s), generating an approximate line attractor in neural state space. Progression of the neural trajectory along this attractor was correlated with an escalation of agonistic behavior, suggesting that it may encode a scalable state of aggressiveness. Consistent with this, individual differences in the magnitude of the integration dimension time constant were strongly correlated with differences in aggressiveness. In contrast, approximate line attractors were not observed in MPOA during mating; instead, neurons with fast dynamics were tuned to specific actions. Thus, different hypothalamic nuclei employ distinct neural population codes to represent similar social behaviors.
Topics: Animals; Sexual Behavior, Animal; Ventromedial Hypothalamic Nucleus; Hypothalamus; Aggression; Social Behavior
PubMed: 36608653
DOI: 10.1016/j.cell.2022.11.027 -
Journal of the Association For Research... Jun 2021The ability to process and perceive sensory stimuli is an essential function for animals. Among the sensory modalities, audition is crucial for communication, pleasure,... (Review)
Review
The ability to process and perceive sensory stimuli is an essential function for animals. Among the sensory modalities, audition is crucial for communication, pleasure, care for the young, and perceiving threats. The auditory cortex (ACtx) is a key sound processing region that combines ascending signals from the auditory periphery and inputs from other sensory and non-sensory regions. The development of ACtx is a protracted process starting prenatally and requires the complex interplay of molecular programs, spontaneous activity, and sensory experience. Here, we review the development of thalamic and cortical auditory circuits during pre- and early post-natal periods.
Topics: Animals; Auditory Cortex; Auditory Perception; Sound; Thalamus
PubMed: 33909161
DOI: 10.1007/s10162-021-00794-3