Biology subjects

Lukinic, E.

Publications and source records attributed to Lukinic, E..

3 recordsLinked to original sources

bioRxiv2026

Prefrontal-medullary circuitry is necessary for sex-specific responses to metabolic stress in rats

Chronic stress increases risk for metabolic disorders, including diabetes mellitus. Additionally, projections from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) regulate endocrine stress responses. However, the neurobiological basis for chronic stress effects on glucose homeostasis has not been identified. The current study tests the hypothesis that the IL-RVLM circuit is necessary to prevent glucose intolerance. Accordingly, male and female rats with Cre-dependent expression of tetanus toxin light chain (TeLC) to inhibit neurotransmitter release from RVLM-projecting IL neurons were subject to chronic variable stress (CVS) or remained as No CVS controls. Animals were then acutely challenged with a fasted intraperitoneal glucose tolerance test (GTT). Endocrine metabolic function was evaluated during GTT via time courses of glucose, insulin, glucagon, and corticosterone. In No CVS females expressing TeLC, inhibition of IL-RVLM circuit signaling impaired glucose tolerance characterized by elevated glucose and decreased insulin sensitivity. Following chronic stress, females had impaired glucoregulation characterized by decreased glucose clearance and elevated corticosterone. When combined with TeLC, chronically-stressed females showed shifts in the ratio of insulin to glucagon compared to CVS GFP females, suggesting circuit function impacts the pancreatic mechanisms mediating glucose homeostasis during chronic stress. In No CVS males, TeLC increased glucagon only. However, CVS TeLC males had impaired glucose tolerance, reduced insulin sensitivity, and decreased corticosterone. These data indicate that the IL-RVLM circuit mediates glucoregulation in a manner dependent on both sex and stress history. Collectively, the IL-RVLM circuit is necessary for the sex-specific maintenance of glucose homeostasis following chronic stress.

neuroscience↗

bioRxiv2025

Infralimbic prefrontal cortical projections to the autonomic brainstem: Quantification of inputs to cholinergic and adrenergic/noradrenergic nuclei

The ventromedial prefrontal cortex regulates both emotional and physiological processes. The infralimbic cortex (IL), a prefrontal subregion in rodents, integrates behavioral, neuroendocrine, and autonomic responses to stress. However, the organization of cortical inputs to brainstem nuclei that regulate homeostatic responses are not well defined. We hypothesized that IL projections differentially target pre-ganglionic parasympathetic neurons and adrenergic/noradrenergic nuclei. To quantify IL projections to autonomic brainstem nuclei in male rats, we utilized viral-mediated gene transfer to express yellow fluorescent protein (YFP) in IL glutamatergic neurons. YFP-positive projections to cholinergic and adrenergic/noradrenergic nuclei were then imaged and quantified. Cholinergic neurons were visualized by immunohistochemistry for choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of acetylcholine. Adrenergic/noradrenergic neurons were visualized with immunohistochemistry for dopamine beta-hydroxylase (DBH) which converts dopamine to norepinephrine. Our results indicate that IL glutamate neurons innervated the cholinergic dorsal motor nucleus of the vagus with greater density than the nucleus ambiguus. Furthermore, numerous DBH-positive cell groups received IL inputs. The greatest density was to the C2 and A2 regions of the nucleus of the solitary tract with intermediate levels of input to A6 locus coeruleus and throughout the C1 and A1 regions of the ventrolateral medulla. Minimal input was present in the pontine A5. Additionally, IL projections targeted the local GABAergic neurons that regulate activity within preautonomic nuclei. Collectively, our results indicate that IL pyramidal neurons project to vagal preganglionic parasympathetic neurons, presympathetic neurons of the ventrolateral medulla, as well as diffuse homeostatic modulators the nucleus of the solitary tract and locus coeruleus. Ultimately, these findings provide a roadmap for determining circuit-level mechanisms for neural control of homeostasis and autonomic balance.

neuroscience↗

bioRxiv2023

Cortical-brainstem circuitry attenuates stress reactivity

Exposure to stressful stimuli promotes multi-system biological responses to restore homeostasis. Catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) facilitate sympathetic activity and promote physiological adaptations, including glycemic mobilization and corticosterone release. While it is unclear how brain regions involved in the cognitive appraisal of stress regulate RVLM neural activity, recent studies found that the rodent ventromedial prefrontal cortex (vmPFC) mediates stress appraisal and physiological stress responses. Thus, a vmPFC-RVLM connection could represent a circuit mechanism linking stress appraisal and physiological reactivity. The current study investigated a direct vmPFC-RVLM circuit utilizing genetically-encoded anterograde and retrograde tract tracers. Together, these studies found that stress-reactive vmPFC neurons project to catecholaminergic neurons throughout the ventrolateral medulla in male and female rats. Next, we utilized optogenetic terminal stimulation to evoke vmPFC synaptic glutamate release in the RVLM. Photostimulating the vmPFC-RVLM circuit during restraint stress suppressed glycemic stress responses in males, without altering the female response. However, circuit stimulation decreased corticosterone responses to stress in both sexes. Circuit stimulation did not modulate affective behavior in either sex. Further analysis indicated that circuit stimulation preferentially activated non-catecholaminergic medullary neurons in both sexes. Additionally, vmPFC terminals targeted medullary inhibitory neurons. Thus, both male and female rats have a direct vmPFC projection to the RVLM that reduces endocrine stress responses, likely through the recruitment of local RVLM inhibitory neurons. Ultimately, the excitatory/inhibitory balance of vmPFC synapses in the RVLM may regulate stress reactivity as well as stress-related health outcomes. First author profileSebastian Pace is a Ph.D. candidate in the laboratory of Brent Myers at Colorado State University. Before beginning his Ph.D., Sebastian completed his B.S. and M.S. at the University of Texas-El Paso. While completing his M.S. he worked in the Karine Fenelon Lab. Sebastians current research project focuses on understanding how corticolimbic inputs to the medullary brainstem regulate sympathetic and neuroendocrine stress responses. Key points summaryO_LIGlutamatergic efferents from the ventromedial prefrontal cortex target catecholaminergic neurons throughout the ventrolateral medulla. C_LIO_LIPartially segregated, stress-responsive ventromedial prefrontal cortex populations innervate the rostral and caudal ventrolateral medulla. C_LIO_LIStimulating ventromedial prefrontal cortex synapses in the rostral ventrolateral medulla decreases stress-induced glucocorticoid release in males and females. C_LIO_LIStimulating ventromedial prefrontal cortex terminals in the rostral ventrolateral medulla preferentially activates non-catecholaminergic neurons. C_LIO_LIVentromedial prefrontal cortex terminals target medullary inhibitory neurons. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/549781v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c362acorg.highwire.dtl.DTLVardef@1830ca5org.highwire.dtl.DTLVardef@b3411borg.highwire.dtl.DTLVardef@779392_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗