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Madara, Joseph

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Madara

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Joseph

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Madara, Joseph
Author's Publications: search.filters.isAuthorOfPublication.40d7286f-ebbf-4c5e-a6d6-0e1fd48b40dc

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Now showing 1 - 7 of 7
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    PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse
    (eLife Sciences Publications, Ltd, 2018) Ross, Rachel; Leon, Silvia; Madara, Joseph; Schafer, Danielle; Fergani, Chrysanthi; Maguire, Caroline A; Verstegen, Anne; Brengle, Emily; Kong, Dong; Herbison, Allan E; Kaiser, Ursula; Lowell, Bradford; Navarro, Victor
    Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) 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 Adcyap1fl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new 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 in female mice.
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    A Novel Excitatory Paraventricular Nucleus to AgRP Neuron Circuit that Drives Hunger
    (2014) Krashes, Michael J.; Shah, Bhavik P.; Madara, Joseph; Olson, David P.; Strochlic, David E.; Garfield, Alastair S.; Vong, Linh; Pei, Hongjuan; Watabe-Uchida, Mitsuko; Uchida, Naoshige; Liberles, Stephen; Lowel, Bradford B.
    Summary Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to its control. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1-5. Consistent with their obligatory role in regulating appetite, genetic ablation or pharmacogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is key in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric state-dependent synaptic plasticity8-10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing Thyrotropin-releasing hormone (TRH) and Pituitary adenylate cyclase-activating polypeptide (PACAP). Pharmaco-genetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
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    Dynamic GABAergic afferent modulation of AgRP neurons
    (2017) Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R; Li, Monica; Li, Chia; Steger, Jennifer S; Madara, Joseph; Campbell, John; Kroeger, Daniel; Scammell, Thomas; Tannous, Bakhos; Myers, Martin G; Andermann, Mark; Krashes, Michael J; Lowell, Bradford
    Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior.
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    A neural basis for melanocortin-4 receptor regulated appetite
    (2015) Garfield, Alastair S.; Li, Chia; Madara, Joseph; Shah, Bhavik P.; Webber, Emily; Steger, Jennifer S.; Campbell, John; Gavrilova, Oksana; Lee, Charlotte E.; Olson, David; Elmquist, Joel K.; Tannous, Bakhos; Krashes, Michael J.; Lowell, Bradford
    Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons are oppositely regulated by caloric depletion and co-ordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) within the paraventricular nucleus of the hypothalamus. Although this population is critical to energy balance the underlying neural circuitry remains unknown. Enabled by mice expressing Cre-recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVHMC4R→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development.
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    A rapidly-acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH
    (2016) Fenselau, Henning; Campbell, John; Verstegen, Anne; Madara, Joseph; Xu, Jie; Shah, Bhavik P.; Resch, Jon; Yang, Zongfang; Mandelblat-Cerf, Yael; Livneh, Yoav; Lowell, Bradford
    Arcuate nucleus (ARC) neurons sense the fed/fasted state and regulate hunger. Agouti-related protein (ARCAgRP) neurons are stimulated by fasting, and once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARCPOMC) neurons are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARCAgRP neurons, ARCPOMC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here, we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVHMC4R neurons). Importantly, transmission across the ARCGlutamatergic→PVHMC4R synapse is potentiated by the ARCPOMC neuron-derived MC4R agonist, α-MSH. This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides new insight into regulation of hunger/satiety.
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    Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit
    (eLife Sciences Publications, Ltd, 2016) D'Agostino, Giuseppe; Lyons, David J; Cristiano, Claudia; Burke, Luke K; Madara, Joseph; Campbell, John; Garcia, Ana Paula; Land, Benjamin B; Lowell, Bradford; Dileone, Ralph J; Heisler, Lora K
    The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite. DOI: http://dx.doi.org/10.7554/eLife.12225.001
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    Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress
    (eLife Sciences Publications, Ltd, 2016) Vernia, Santiago; Morel, Caroline; Madara, Joseph; Cavanagh-Kyros, Julie; Barrett, Tamera; Chase, Kathryn; Kennedy, Norman J; Jung, Dae Young; Kim, Jason K; Aronin, Neil; Flavell, Richard A; Lowell, Bradford; Davis, Roger J
    The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress. DOI: http://dx.doi.org/10.7554/eLife.10031.001