Biology subjects

Krashes, M. J.

Publications and source records attributed to Krashes, M. J..

8 recordsLinked to original sources

bioRxiv2026

Thermoregulatory roles of preoptic area histamine H1 receptor-expressing neurons

The preoptic area (POA) is a key regulator of body temperature, orchestrating behavioral and physiological thermoregulatory functions, including fever, torpor, and homeostatic responses to ambient temperature. Histamine regulates body temperature across animal taxa, including mammals, lower vertebrates, and invertebrates. Hrh1, which encodes the histamine H1 receptor, is expressed in several neuronal populations in the POA with limited overlap with other POA thermoregulatory neurons. Acute activation of POAHrh1 neurons increased body temperature and physical activity. Acute inhibition attenuated the dark phase increase in body temperature without affecting physical activity. There was no effect of inhibition on body temperature during the light phase, fever, cold exposure, or warm exposure. Assessing behavioral thermoregulation, we found that POAHrh1 neurons stimulated nest building in both sexes, possibly contributing to cold-induced nesting behavior. Through projections to the arcuate, dorsomedial hypothalamic and tuberomammillary nuclei, POAHrh1 neurons can increase body temperature and physical activity. Overall, POAHrh1 neurons participate in several thermoregulatory functions, including daily body temperature rhythm regulation, physical activity, and nest building behavior.

neuroscience↗

bioRxiv2025

Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons

Glucagon-like peptide 1 receptor (GLP1R) agonists like semaglutide drive weight loss through the brain, but insights into their intracellular signaling mechanisms are lacking. Although canonically GLP1Rs signal through the stimulatory alpha Gs protein, we find that semaglutide utilizes both Gs- and Gq-signaling pathways in GLP1Rs in the area postrema (AP)--the primary site of semaglutide action in the brain--to differentially regulate neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in Glp1r-expressing AP neurons (APGlp1r) through Gs-dependent and -independent manners. Inhibition of the cAMP-degradation enzyme phosphodiesterase 4 (PDE4) can enhance and sustain these cAMP responses, whereas disruption of Gs or cAMP signaling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutides signaling mechanisms in the brain provides avenues for improving the performance of obesity therapeutics.

neuroscience↗

bioRxiv2024

A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.

neuroscience↗

bioRxiv2023

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

neuroscience↗

bioRxiv2021

An essential role for a discrete parasubthalamic nucleus subpopulation in appetite suppression

Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an essential role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, is sufficient to reduce food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an essential, anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.

neuroscience↗

bioRxiv2021

AgRP neurons coordinate the mitigation of activity-based anorexia

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented body weight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Moreover, while exercise has been shown to diminish the activity of hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons, much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals revealed a maladaptive inhibitory response to food. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

neuroscience↗

bioRxiv2021

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

The preoptic area (POA) is a key region controlling body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses to regulate Tb. Known POA neuronal populations reduce Tb when activated; a population that increases Tb upon activation has not yet been reported. We now identify bombesin-like receptor 3 (BRS3)-expressing POA (POABRS3) neurons as having this missing functionality. BRS3 is an orphan receptor that regulates energy and cardiovascular homeostasis, but the relevant neural circuits are incompletely understood. In mice, we demonstrate that POABRS3 neuronal activation increases Tb, heart rate, and blood pressure sympathetically, via projections to the paraventricular nucleus of the hypothalamus and dorsomedial hypothalamus. Acute POABRS3 inhibition reduces Tb. Long-term inactivation of POABRS3 neurons increased Tb variability with exaggerated Tb changes, overshooting both increases and decreases in Tb set point. BRS3 marks preoptic populations that regulate Tb and heart rate, contribute to cold-defense and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/433948v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@121b5a8org.highwire.dtl.DTLVardef@1d67bforg.highwire.dtl.DTLVardef@865eeborg.highwire.dtl.DTLVardef@1c1d41e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2019

A role for the locus coeruleus in the modulation of feeding

Recent data suggest that LC-NE neurons play a role in fear-induced suppression of feeding, but their endogenous activity in naturally behaving animals has not been explored. We found that endogenous activity of LC-NE neurons was enhanced during food approach and suppressed during food consumption, and that these food-evoked LC-NE responses were attenuated in sated mice. Interestingly, visual-evoked LC-NE activity was also attenuated in sated mice, demonstrating that internal satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Lastly, we demonstrated that activation of LC neurons suppresses feeding and enhances avoidance and anxiety-like responding through a projection to the lateral hypothalamus. Collectively, our data suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., nutritional state).

neuroscience↗