Biology subjects

Rinaman, L.

Publications and source records attributed to Rinaman, L..

8 recordsLinked to original sources

bioRxiv2024

An ascending vagal sensory-central noradrenergic pathway modulates retrieval of passive avoidance memory

BackgroundVisceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay "gut feelings" to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. ResultsTo examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. ConclusionsThese new findings support the view that a gut vagal afferent-to-cNTSNA-to-vlBNST circuit plays a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

neuroscience↗

bioRxiv2022

A Cre-Driver Rat Model for Anatomical and Functional Analysis of Glucagon (Gcg)-Expressing Cells in the Brain and Periphery

ObjectiveThe glucagon gene (Gcg) encodes preproglucagon, which is cleaved to form glucagon-like peptide 1 (GLP1) and other mature signaling molecules implicated in metabolic functions. To date there are no transgenic rat models available for precise manipulation of GLP1-expressing cells in the brain and periphery. MethodsTo visualize and manipulate Gcg-expressing cells in rats, CRISPR/Cas9 was used to express iCre under control of the Gcg promoter. Gcg-Cre rats were bred with tdTomato reporter rats to tag Gcg-expressing cells. Cre-dependent AAVs and RNAscope in situ hybridization were used to evaluate the specificity of iCre expression by GLP1 neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt), and by intestinal and pancreatic secretory cells. Food intake was assessed in heterozygous (Het) Gcg-Cre rats after chemogenetic stimulation of cNTS GLP1 neurons expressing an excitatory DREADD. ResultsWhile genotype has minimal effect on body weight or composition in chow-fed Gcg-Cre rats, homozygous (Homo) rats have lower plasma glucose levels. In neonatal and adult Gcg-Cre/tdTom rats, reporter-labeled cells are present in the cNTS and IRt, and in additional brain regions (e.g., basolateral amygdala, piriform cortex) that lack detectable Gcg mRNA in adults but display transient developmental or persistently low Gcg expression. Compared to wildtype (WT) rats, hindbrain Gcg mRNA and GLP1 protein in brain and plasma are markedly reduced in Homo Gcg-Cre rats. Chemogenetic stimulation of cNTS GLP1 neurons reduced overnight chow intake in males but not females, the effect in males was blocked by antagonism of central GLP1 receptors, and hypophagia was enhanced when combined with a subthreshold dose of cholecystokinin-8 to stimulate gastrointestinal vagal afferents. ConclusionsGcg-Cre rats are a novel and valuable experimental tool for analyzing the development, anatomy, and function of Gcg-expressing cells in the brain and periphery. In addition, Homo Gcg-Cre rats are a unique model for assessing the role of Gcg-encoded proteins in glucose homeostasis and energy metabolism. HighlightsO_LIA transgenic Gcg-Cre rat model expresses iCre under control of the Gcg promoter C_LIO_LIiCre is expressed by GLP1-positive cells in the hindbrain, pancreas, and intestine C_LIO_LIAdditional brain regions display transient and/or very low levels of Gcg expression C_LIO_LI+/+ Gcg-Cre rats display a marked knockdown of Gcg mRNA and GLP1 protein C_LIO_LIChemogenetic activation of Gcg neurons suppresses food intake in +/- Gcg-Cre rats C_LI

neuroscience↗

bioRxiv2022

Ghrelin receptor signaling contributes to fasting-induced suppression of conditioned avoidance behavior and neural circuit activation in male rats

Interoceptive feedback to the brain regarding the bodys physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. To test this, ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. GRA restored passive avoidance in fasted rats as measured both by latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before re-exposure to the shock-paired context displayed more activation of prolactin-releasing peptide (PrRP)-positive noradrenergic neurons in the caudal nucleus of the solitary tract, accompanied by more activation of downstream neurons in the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus. These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive noradrenergic neurons and their downstream hypothalamic and limbic forebrain targets.

neuroscience↗

bioRxiv2022

Modulation of stress-related behaviour by hypothalamic engagement of preproglucagon neurons in the nucleus of the solitary tract

Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that a corticotropin-releasing hormone (CRH)-rich input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute stress. Finally, we demonstrate that NTS-projecting PVN neurons are necessary for the ability of acute stress to suppress food intake. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.

neuroscience↗

bioRxiv2021

Glucagon-like peptide 1 receptor-mediated stimulation of a GABAergic projection from the bed nucleus of the stria terminalis to the hypothalamic paraventricular nucleus

We previously reported that GABAergic neurons within the ventral anterior lateral bed nucleus of the stria terminalis (alBST) express glucagon-like peptide 1 receptor (GLP1R) in rats, and that virally-mediated "knock-down" of GLP1R expression in the alBST prolongs the hypothalamic-pituitary-adrenal axis response to acute stress. Given other evidence that a GABAergic projection pathway from ventral alBST serves to limit stress-induced activation of the HPA axis, we hypothesized that GLP1 signaling promotes activation of GABAergic ventral alBST neurons that project directly to the paraventricular nucleus of the hypothalamus (PVN). After PVN microinjection of fluorescent retrograde tracer followed by preparation of ex vivo rat brain slices, whole-cell patch clamp recordings were made in identified PVN-projecting neurons within the ventral alBST. Bath application of Exendin-4 (a specific GLP1R agonist) indirectly depolarized PVN-projecting neurons in the ventral alBST and adjacent hypothalamic parastrial nucleus (PS) via circuit-mediated effects that increased excitatory synaptic inputs and decreased inhibitory synaptic inputs to the PVN-projecting neurons; these effects were occluded by prior bath application of a GLP1R antagonist. Additional retrograde tracing experiments combined with in situ hybridization confirmed that PVN-projecting neurons within the ventral alBST/PS are GABAergic, and do not express GLP1R mRNA. Conversely, GLP1 mRNA is expressed by a subset of GABAergic neurons within the oval subnucleus of the dorsal alBST that project into the ventral alBST. Our novel findings reveal a potential GLP1R-mediated mechanism through which the alBST exerts inhibitory control over the endocrine HPA axis.

neuroscience↗

bioRxiv2021

Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons

Competing motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fed ad libitum prior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. Overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.

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bioRxiv2020

Central and peripheral GLP-1 systems independently and additively suppress eating

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which respectively define the peripheral and central GLP-1 systems. As peripheral satiation signals are integrated in the nucleus tractus solitarius (NTS), PPGNTS neurons are assumed to link the peripheral and central GLP-1 systems, forming a unified GLP-1 gut-brain satiation circuit. This hypothesis, however, remains unsubstantiated. We report that PPGNTS neurons encode satiation in mice, consistent with vagal gastrointestinal distension signalling. However, PPGNTS neurons predominantly receive vagal input from oxytocin receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. Furthermore, PPGNTS neurons are not necessary for eating suppression induced by the GLP-1 receptor agonists liraglutide or semaglutide, and semaglutide and PPGNTS neuron activation additively suppress eating. Central and peripheral GLP-1 systems thus suppress eating via independent gut-brain circuits, hence PPGNTS neurons represent a rational pharmacological target for anti-obesity combination therapy with GLP-1 receptor agonists. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/234427v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1c7643aorg.highwire.dtl.DTLVardef@18520daorg.highwire.dtl.DTLVardef@12fc8fdorg.highwire.dtl.DTLVardef@34809b_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: C_FIG

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bioRxiv2017

Burst Activation Of Dopamine Neurons Produces Prolonged Post-Burst Availability Of Actively Released Dopamine

Both phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (> 20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.

neuroscience↗