Biology subjects

Lutas, A.

Publications and source records attributed to Lutas, A..

11 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↗

bioRxiv2025

An amygdalopontine pathway promotes motor programs of ingestion

Despite internal cues that signal fullness, animals can continue eating when motivated by context or palatability. The neural pathways and signals that enable animals to override these fullness cues remain unclear. We examined a central amygdala (CeA) projection to the dorsolateral pons that targets the parabrachial nucleus, a well-established meal termination center, and the adjacent supratrigeminal nucleus, a region that controls orofacial movements. Activity in this CeApons pathway correlated with the animals licking behavior but was not modulated by metabolic need or palatability cues. CeApons stimulation caused animals to overeat, consume non-edible objects within reach, or exhibit ingestion-like behaviors--licking, chewing, and grasping--even when no target was present. Depending on training and context, stimulation elicited either licking or pellet consumption, suggesting that CeApons promotes a flexible, goal-directed ingestive state by recruiting consummatory motor circuits rather than simply suppressing satiety signals. These findings highlight how forebrain-brainstem interactions can re-engage feeding behavior beyond homeostatic need.

neuroscience↗

bioRxiv2025

Cocaine-induced immediate-early gene expression in the nucleus accumbens: roles of separate cAMP sensors

Immediate-early gene (IEG) induction after administration of amphetamine or cocaine has been used to trace the signaling pathways that mediate neuronal plasticity required for the short- and long-term behavioral effects of these psychostimulants. We recently reported that a novel cyclic AMP (cAMP)-dependent Rap guanine nucleotide exchange factor-2 (RapGEF2)-ERK signaling pathway is required for Egr-1 induction in D1 medium-spiny neurons (MSNs) of the nucleus accumbens (NAc) after cocaine treatment, and that its deletion from the NAc neurons attenuates cocaine-induced locomotor sensitization and conditioned place preference (CPP). However, the cell type-specific neuronal mechanisms underlying this effect remain unclear. In this study, we used Cre-LoxP technology and a novel Cre-amplifier transgene to generate conditional RapGEF2 knockout mice targeting D1-MSNs and investigated the functional role of RapGEF2 in cocaine reward. Deletion of RapGEF2 in D1-MSNs blocked cocaine-induced ERK phosphorylation (p-ERK) and Egr-1 induction. D1-MSN-specific RapGEF2 deletion did not affect intravenous cocaine self-administration, nor did it affect Fos induction by cocaine, prompting us to examine more closely the role of metabotropic (cAMP-dependent) signaling to IEGs after cocaine administration. We used a battery of D1-MSN-specific genetic interventions targeting cAMP signaling, including Drd1-Cre::Rap1A/Bfl/fl mice, and AAV injection of a Cre-dependent catalytically active phosphodiesterase (PDE4D3-cat) or a Cre-dependent protein kinase A-inhibitor (PKI) in the NAc of Drd1-Cre mice, to explore further the underlying cAMP dependence of IEG induction by acute and chronic cocaine administration, and the cAMP sensors required. Rap1 is reported as a necessary component for both RapGEF2- and PKA-dependent ERK activation, but a requirement for Rap in Fos induction by cocaine has not been examined. Deletion of Rap1A/B in D1-MSNs blocked cocaine-induced p-ERK and Egr-1 expression, but not c-Fos, supporting the idea that the RapGEF2-Rap1-ERK pathway specifically regulates Egr-1, not c-Fos, expression. D1-specific expression of the PDE4D3-cat ablated up-regulation of both Egr-1 and Fos in NAc after cocaine administration, demonstrating that induction of both IEGs requires cAMP elevation in D1-MSNs. Notably, inhibition of PKA activity via AAV-mediated expression of PKI-alpha in D1-MSNs blocked both c-Fos and Egr-1 induction. Thus, acute or chronic cocaine administration activates at least two cAMP-dependent signaling pathways in D1-MSNs: a PKA-Fos pathway and a RapGEF2-ERK-Egr-1 pathway. The finding that PKA also activates the ERK-Egr-1 signaling pathway by convergence on Rap1, and concomitantly activates c-Fos independently of Rap1, may underlie selective effects of metabotropic activation of RapGEF2 and PKA activation by cAMP on cocaine-dependent behaviors in mice.

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↗

bioRxiv2023

Competition between stochastic neuropeptide signals calibrates the rate of satiation

We investigated how transmission of hunger- and satiety-promoting neuropeptides, NPY and MSH, is integrated at the level of intracellular signaling to control feeding. Receptors for these peptides use the second messenger cAMP, but the messengers spatiotemporal dynamics and role in energy balance are controversial. We show that AgRP axon stimulation in the paraventricular hypothalamus evokes probabilistic and spatially restricted NPY release that triggers stochastic cAMP decrements in downstream MC4R-expressing neurons (PVHMC4R). Meanwhile, POMC axon stimulation triggers stochastic, MSH-dependent cAMP increments. NPY and MSH competitively control cAMP, as reflected by hunger-state-dependent differences in the amplitude and persistence of cAMP transients evoked by each peptide. During feeding bouts, elevated MSH release and suppressed NPY release cooperatively sustain elevated cAMP in PVHMC4R neurons, thereby potentiating feeding-related excitatory inputs and promoting satiation across minutes. Our findings highlight how state-dependent integration of opposing, quantal peptidergic events by a common biochemical target calibrates energy intake.

neuroscience↗

bioRxiv2023

Chronic stress triggers seeking of a starvation-like state in anxiety-prone female mice

Elevated anxiety often precedes anorexia nervosa and persists after weight restoration. Patients with anorexia nervosa often describe hunger as pleasant, potentially because food restriction can be anxiolytic. Here, we tested whether chronic stress can cause animals to prefer a starvation-like state. We developed a virtual reality place preference paradigm in which head-fixed mice can voluntarily seek a starvation-like state induced by optogenetic stimulation of hypothalamic agouti-related peptide (AgRP) neurons. Prior to stress induction, male but not female mice showed mild aversion to AgRP stimulation. Strikingly, following chronic stress, a subset of females developed a strong preference for AgRP stimulation that was predicted by high baseline anxiety. Such stress-induced changes in preference were reflected in changes in facial expressions during AgRP stimulation. Our study suggests that stress may cause females predisposed to anxiety to seek a starvation state, and provides a powerful experimental framework for investigating the underlying neural mechanisms.

neuroscience↗

bioRxiv2023

Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons tosuppress feeding

Brief stimuli can trigger longer lasting brain states. G protein-coupled receptors (GPCRs) could help sustain such states by coupling slow-timescale molecular signals to neuronal excitability. Brainstem parabrachial nucleus glutamatergic neurons (PBNGlut) regulate sustained brain states such as pain, and express Gs-coupled GPCRs that increase cAMP signaling. We asked whether cAMP directly influences PBNGlut excitability and behavior. Both brief tail shocks and brief optogenetic stimulation of cAMP production in PBNGlut neurons drove minutes-long suppression of feeding. This suppression matched the duration of prolonged elevations in cAMP, Protein Kinase A (PKA), and calcium activity in vivo and in vitro. Shortening this elevation in cAMP reduced the duration of feeding suppression following tail shocks. cAMP elevations in PBNGlut neurons rapidly lead to sustained increases in action potential firing via PKA-dependent mechanisms. Thus, molecular signaling in PBNGlut neurons helps prolong neural activity and behavioral states evoked by brief, salient bodily stimuli.

neuroscience↗

bioRxiv2022

Cortical reactivations predict future sensory responses

Prevailing theories of offline memory consolidation posit that the pattern of neurons activated during a salient sensory experience will be faithfully reactivated, thereby stabilizing the entire pattern1-3. However, sensory-evoked patterns are not stable, but instead drift across repeated experiences4-7. To investigate potential roles of reactivations in the stabilization and/or drift of sensory representations, we imaged calcium activity of thousands of excitatory neurons in mouse lateral visual cortex. Presentation of a stimulus resulted in transient, stimulus-specific reactivations during the following minute. These reactivations depended on local circuit activity, as they were abolished by local silencing during the preceding stimulus. Contrary to prevailing theories, reactivations systemically differed from previous patterns evoked by the stimulus. Instead, they were more similar to future patterns evoked by the stimulus, thereby predicting representational drift. In particular, neurons that participated more or less in early reactivations than in stimulus response patterns subsequently increased or decreased their future stimulus responses, respectively. The rate and content of these reactivations was sufficient to accurately predict future changes in stimulus responses and, surprisingly, the decreasing similarity of responses to distinct stimuli. Thus, activity patterns during sensory cortical reactivations may guide the drift in sensory responses to improve sensory discrimination8.

neuroscience↗

bioRxiv2021

Dopamine-dependent cAMP dynamics in basal amygdala glutamatergic neurons

Dopaminergic inputs to basal amygdala (BA) instruct learning of motivational salience. Here, we investigated the dynamics of dopamine release and downstream signaling during multiple salient events occurring within tens of seconds. We established in vitro and in vivo real-time tracking and manipulation of cAMP - a key intracellular plasticity signal downstream of dopamine receptor activation. Optogenetically-evoked release of dopamine drove proportional increases in cAMP in almost all BA glutamatergic neurons, suggesting widespread actions of dopamine across neurons preferring positive or negative valence. These cAMP responses decayed more slowly than dopamine release, potentially extending the window of plasticity. cAMP levels accumulated following direct photostimulation of cAMP but not repeated stimulation of dopamine axons, due to potent depression of dopamine release. cAMP and protein kinase A (PKA) responses to repeated appetitive or aversive stimuli also exhibited pronounced depression. Thus, history-dependent dynamics of dopamine and cAMP may regulate learning of temporally clustered, salient stimuli.

neuroscience↗

bioRxiv2019

State-specific gating of salient cues by midbrain dopaminergic input to basal amygdala

Basal amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area dopamine axons that innervate BA (VTADA[->]BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA[->]BA axons were activated by both rewards and punishments, and acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA[->]BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA[->]BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.

neuroscience↗