Biology subjects

Madara, J. C.

Publications and source records attributed to Madara, J. C..

7 recordsLinked to original sources

bioRxiv2025

A hypothalamic circuit for anticipating future changes in energy balance.

AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons, since cues that predict future food intake rapidly inhibit AgRP neurons. But is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here we show that such rapid fasting activation of AgRP neurons does occur. This fasting response is driven by excitatory input from paraventricular hypothalamic neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. In this way, cognitively-processed contextual information conveyed by PVHSim2 neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVHSim2 neurons causes persistent hypophagia. This PVHSim2 to AgRP neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.

neuroscience↗

bioRxiv2025

Slow-Timescale Regulation of Dopamine Release and Mating Drive over Days

The rise and fall of motivational states may take place over timescales as long as many days. We used mouse mating behavior to model how the brain orchestrates slow-timescale changes in motivation. Male mice become sexually satiated after successful matings, and their motivation to mate gradually recovers over a week. Using deep-brain fluorescence-lifetime imaging in the medial preoptic area (MPOA), we found that tonic dopamine transmission--which regulates mating drive--also declined after mating and re-emerged over a week. Two mechanisms regulated dopamine transmission. First, successful mating transiently reduced tonic firing of hypothalamic dopamine-releasing neurons, thereby inhibiting dopamine release and mating behavior. Second, mating reduced the ability of these neurons to produce and release dopamine, and this ability gradually returned over the week-long recovery time course. Therefore, fast and slow mechanisms of neuronal plasticity cooperate to control the early and late phases of motivational dynamics, respectively.

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

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↗

bioRxiv2021

Neural Basis for Regulation of Vasopressin Secretion by Anticipated Disturbances in Osmolality

Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality are detected. Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality are anticipated. Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking and eating, which will ultimately decrease and increase osmolality. Here, we demonstrate that AVP neuron activity is regulated by multiple anatomically-and functionally-distinct neural circuits. Notably, presystemic regulation during drinking and eating are mediated by non-overlapping circuits that involve the lamina terminalis and hypothalamic arcuate nucleus, respectively. These findings reveal neural mechanisms that support differential regulation of AVP release by diverse behavioral and physiological stimuli.

physiology↗

bioRxiv2020

AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes

Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon - the bodys principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in isolated islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

cell biology↗

bioRxiv2018

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with PACAPfl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new, sex-specific role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction.

neuroscience↗