The McIntyre Lab is part of the Department of Neuroscience, the University Center for Smell and Taste and the Center for Addiction Research and Education at the University of Florida College of Medicine. We study the cellular and molecular mechanisms that underlie neuromodulation of sensory and reward pathways. The lab is interested in hypothalamic neurons that project to the olfactory bulb and reward areas of the brain. As part of this we are investigating how the peptide, melanin-concentrating hormone changes how odor information is processed in the olfactory bulb, or how an animal responds to psycho-stimulants. We are particularly focused on the role that the primary cilium plays in serving as a signaling platform for this peptide. We use employ a wide variety of techniques including AAV mediated gene delivery, immunohistochemistry and confocal microscopy, calcium imaging, molecular and cell biology, and transgenic mouse models.
Cilia mediated neuromodulation of reward pathways
Substance use disorders are a significant health issue in the US, costing tens of thousands of lives and hundreds of billions of dollars annually. The neural mechanisms that underlie substance use disorders are complex, and impacted by numerous outside factors. These additional actors include several neuromodulatory peptides that are associated with physiological states such as hunger and satiety. Within the past ten years it has been discovered that several of the receptors for these neuromodulators are enriched in the primary cilia of neurons. The goal of this research is to determine how signaling through the primary cilium contributes to integration of neuromodulatory signals that regulate responsiveness to drugs of abuse and related behaviors. We are using pharmacological and viral-mediated gene delivery approaches to study the role of cilia on GABAergic and dopaminergic neruons in regulating these behaviors. We are interested in understanding the consequences of cilia loss, particularly in the nucleus accumbens, for the rewarding effects of cocaine and morphine. In addition to using ciliary signaling to identify novel modulators of these behaviors. This project uses a variety of techniques including behavior experiments, viral manipulations, calcium imaging and microscopy. Cilia represent a unique neuronal signaling environment and a better understanding of this could lead to novel targets for therapies aimed at reducing substance use.
Primary Cilia function on olfactory bulb neurons
Primary cilia are ubiquitous organelles found on many cell types, including neurons of the CNS. These structures are a type of cellular “antenna” that function to sense cues in the extracellular environment. However the precise roles for these organelles on neurons in the brain remain unknown. Many of these cilia possess G-protein coupled receptors for neuromodulatory signals. We are working to identify the particular GPCRs found in the cilia of different subtypes of olfactory bulb neurons. We will be using calcium imaging, electrophysiology and behavior testing to analyze the importance of cilia, and the receptors localized there, on these neurons.
Hypothalamus mediated modulation of the olfactory bulb
Olfactory processing is influenced by the physiological state of an organism. Both sleep deprivation and changes in satiety are connected with changes in the function of the olfactory system. Physiological changes such as these are integrated in the hypothalamus, where different neuropeptides are expressed by specific populations of neurons. These peptides can regulate transitions between wakefulness and sleep, or promote feeding behaviors. One peptide that functions in both promoting feeding and sleep is melanin-concentrating hormone (MCH). Neurons expressing MCH project to several areas of the brain including the olfactory bulb (OB), where the MCH receptor, MCHR1, is expressed. This connection represents a previously understudied pathway providing a potential mechanism for sleep or satiety induced changes in olfactory function. This project focuses on the role MCH and MCHR1 play in modulating the sense of smell. We are using opto- and chemogenetic approaches to map the connectivity between the hypothalamus and the bulb. Behavioral, immunohistochemical and biochemical approaches are used to look at how physiological states impact MCH levels in the bulb and how this influences sensory perception.