Biology subjects

Halpern, M. E.

Publications and source records attributed to Halpern, M. E..

5 recordsLinked to original sources

bioRxiv2025

Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding

The lateral hypothalamus (LH) is a highly heterogeneous brain region regulating hunger and motivated behaviors. In zebrafish, the LH shows distinct neural activity across hunger, feeding, and satiety states. However, the functional and evolutionary conservation of relevant neural circuits remain unclear. Using integrative transcriptomics of zebrafish and mouse LH, we identify conserved cellular clusters with shared molecular markers, particularly within GABAergic neurons. We highlight a conserved GABAergic population expressing tachykinin and growth hormone receptors, which is responsive to food cues and modulated by hunger and feeding states. This cluster may mediate acute appetite-enhancing effects of growth hormone. In both species, feeding elevates growth hormone receptor and tachykinin expression and activates these neurons, while human growth hormone increases their activity and food intake in zebrafish. These findings suggest a conserved neural mechanism by which metabolic hormones influence feeding behavior. Our comparative LH atlas highlights the evolutionary biology of appetite regulation and the integration of hormonal and neural signals driving energy homeostasis.

neuroscience↗

bioRxiv2024

A cleaved cytosolic FOXG1 promotes excitatory neurogenesis by modulation of mitochondrial translation - a new therapeutic target for brain disorders.

The modulation of mitochondrial function is core to cell fate decisions and tissue homeostasis, yet the mechanisms regulating these processes remain poorly understood. Here, we demonstrate that mitochondrial OXPHOS activity is controlled in a tissue-specific manner through a non-canonical cytoplasmic function of the transcription factor FOXG1. A temporally regulated short cytoplasmic FOXG1 interacts with mitochondrial ribosomal proteins and enhances translation of mt-DNA-encoded OXPHOS proteins. Zebrafish and human models of early nonsense FOXG1 syndrome mutations unexpectedly produce a short C-terminal peptide. Expression of this truncated protein drives an overproduction of excitatory neurons and induces a structural, functional, and translational phenotype in mutant mitochondria. We demonstrate that this activity is a gain of function, normally carried out by a cleaved FOXG1 in wildtype. Both normal and mutant peptides are transported to the mitochondria, interact with mito-ribosomal proteins to enhance translation, thereby stimulating neurogenesis. Adjusting the dosage of the mutant peptide rescues the excitatory aspect of the FOXG1 syndrome. Our study demonstrates a novel role for cytoplasmic Foxg1 in promoting neurogenesis via the tuning of mitochondrial translation and provides the first evidence for direct tissue-specific control of OXPHOS activity. This study opens a novel therapeutic avenue for the treatment of disorders associated with mitochondrial hypoactivity. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/607559v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b8806forg.highwire.dtl.DTLVardef@1f81e3forg.highwire.dtl.DTLVardef@89d9e1org.highwire.dtl.DTLVardef@3f7a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Transsynaptic labeling and transcriptional control of zebrafish neural circuits

Deciphering the connectome, the ensemble of synaptic connections that underlie brain function, is a central goal of neuroscience research. Here, we report mapping of connections between presynaptic and postsynaptic partners in a living vertebrate nervous system, that of the zebrafish, through the successful adaptation of the trans-Tango genetic approach, first developed for anterograde transsynaptic tracing in Drosophila. Neural connections were visualized between synaptic partners in the larval retina and brain and followed over development. Results were corroborated by functional experiments in which optogenetic activation of retinal ganglion cells elicited responses in neurons of the optic tectum, as measured by trans-Tango-dependent expression of a genetically encoded calcium indicator. Transsynaptic signaling through trans-Tango reveals predicted as well as previously undescribed synaptic connections in the zebrafish brain, providing a valuable in vivo tool to monitor and interrogate neural circuits over time.

neuroscience↗

bioRxiv2022

Genetically defined nucleus incertus neurons differ in connectivity and function

The nucleus incertus (NI), a conserved hindbrain structure implicated in the stress response, arousal, and memory, is a major site for production of the neuropeptide relaxin-3. On the basis of goosecoid homeobox 2 (gsc2) expression, we identified a neuronal cluster that lies adjacent to relaxin 3a (rln3a) neurons in the zebrafish analogue of the NI. To delineate the characteristics of the gsc2 and rln3a NI neurons, we used CRISPR/Cas9 targeted integration to drive gene expression specifically in each neuronal group, and found that they differ in their efferent and afferent connectivity, spontaneous activity, and functional properties. gsc2 and rln3a NI neurons have widely divergent projection patterns and innervate distinct subregions of the midbrain interpeduncular nucleus (IPN). Whereas gsc2 neurons are activated by electric shock, rln3a neurons exhibit spontaneous fluctuations in calcium signaling and regulate locomotor activity. Our findings define heterogeneous neurons in the NI and provide new tools to probe its diverse functions.

neuroscience↗

bioRxiv2021

Specialized neurons in the right habenula mediate response to aversive olfactory cues

Hemispheric specializations are well studied at the functional level but less is known about the underlying neural mechanisms. We identified a small cluster of cholinergic neurons in the right dorsal habenula (dHb) of zebrafish, defined by their expression of the lecithin retinol acyltransferase domain containing 2a (lratd2a) gene and their efferent connections with a subregion of the ventral interpeduncular nucleus (vIPN). The unilateral lratd2a-expressing neurons are innervated by a subset of mitral cells from both the left and right olfactory bulb and are activated upon exposure of adult zebrafish to the aversive odorant cadaverine that provokes avoidance behavior. Using an intersectional strategy to drive expression of the botulinum neurotoxin specifically in these neurons, we find that adults no longer show protracted avoidance to cadaverine. Mutants with left-isomerized dHb that lack these neurons are less repelled by cadaverine and their behavioral response to alarm substance, a potent aversive cue, is diminished. However mutants in which both dHb have right identity appear more reactive to alarm substance. The results implicate an asymmetric dHb-vIPN neural circuit in processing of aversive olfactory cues and modulating resultant behavioral responses.

neuroscience↗