S7 – Neuropeptides: from molecules to behavior

This symposium aims to discuss the different neuropeptides system’s recent molecular and behavioral regulations. It will explore the peptide’s role under several physiological, pathophysiological, and programming conditions and the central and peripheral effects of those neuropeptides, and the sex differences. The speakers will present data acquired using state-of-art techniques, such as electrophysiological and blood pressure recordings, microdialysis, real-time PCR, proteome, single-nucleus RNAseq, and pharmacological approaches. Dr. Sotomayor-Zárate will talk about the role of the glucagon-like peptide-1 system in homeostatic and hedonic control of feeding. Dr. Renard will talk about the role of vasopressin in addictive behaviors and the regulation of the reward system. Dr. Mecawi Will talk about the transcriptional conservation and divergence in oxytocin and vasopressin-producing hypothalamic magnocellular neurons across evolution. Finally, Dr. Godino will talk about the effect of programming vasopressin magnocellular cells on osmoregulatory responses.

Obesity is a global pandemic that generates significant health costs associated with developing chronic diseases such as hypertension, dyslipidemia, and diabetes. A behavioral characteristic in obese patients is hyperphagia, which accounts for dysregulations in the brain circuits that control homeostatic and hedonic food intake. Feeding control is regulated by hypothalamic and extra-hypothalamic areas such as the lateral septum (LS). The Glucagon-like peptide-1 (GLP-1) system has taken great relevance in controlling food intake, and LS expresses the GLP-1 receptor. In addition, LS GABAergic projections regulate the activity of the lateral hypothalamus (LH) and ventral tegmental area (VTA), which are involved in homeostatic and hedonic control of feeding, respectively.
At a neurochemical level, we have shown that the release of GABA in LH mediated by the activation of LS neurons is lower in high-fat diet (HFD) male and female rats than in control rats. We indicate a lower activation of this nucleus in a diet-induced obesity model. Regarding sex differences, we have shown that females expressed higher levels of GLP-1 receptor in the LS than males, and females subjected to an HFD have lower LS GLP-1 receptor levels than control females. Interestingly, treatment with a GLP-1 analog reverted this change. Electrophysiological studies performed on slices in LS and nucleus accumbens (NAcc) showed a reduced probability of glutamate release in LS from males exposed to HFD, accounting for the lower GABA release in LH observed in HFD rats.
In this context, our research demonstrated that this chronic exposure to a high-fat diet decreases the activity of GABAergic neurons in the LS, which results in lower regulatory activity in another brain area known as the hunger center (lateral hypothalamus [LH]). Therefore, the functional and neurochemical deregulation, together with altered gene and protein expression patterns in the LS, accounts for the characteristic hyperphagia of patients with obesity, which could be partly due to this lower activity of the LS on LH. This evidence makes LS an attractive pharmacological target for searching for new treatments to combat this global pandemic.

Ramón Sotomayor-Zárate
ramon.sotomayor@uv.cl
Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
https://www.neurobiologia.cl/investigadores/ramon-sotomayor-z/

Drug addiction is a chronic brain disease characterized by compulsive use of drugs. Amphetamine (AMPH) is a psychoactive substance commonly used as a recreational drug by young people, and there is a lack of effective medications for the treatment of AMPH or other psychostimulant addiction. Recent studies have shown that the vasopressin (AVP) system plays a significant role in drug addiction, making it an interesting therapeutic target. The lateral septum (LS) is a brain structure implicated in addictive behaviors, regulating the activation of dopamine (DA) neurons in the ventral tegmental area (VTA), therefore modulating the reward system. Extended amygdala vasopressin (AVP) projections to LS are sexually dimorphic and could be responsible for the vulnerability to addiction in a sex-dependent manner. Our work aimed to study the effect of LS AVP system modulation on AMPH-induced behavioral and neurochemical responses in female and male rats. We showed that AVP microinjection in LS reduces the expression of AMPH-induced conditioned place preference (CPP) in male and female rats. However, this behavior is only associated with lower nucleus accumbens (NAc) DA release in male rats. Also, intra-LS AVP administration increases LS GABA release and decreases VTA DA release only in male rats. Interestingly, our data demonstrate that intra-LS AVP reduces AMPH-induced CPP in rats of both sexes; however, at the neurochemical level, we observed sex differences. This research contributes to the knowledge about sex differences in the role of AVP in LS in regulating the reward circuit and addictive-like behaviors.

Georgina María Renard
georgina.renard@usach.cl
Centro de Investigación Biomédica Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile
https://cibap.usach.cl/es/georgina-m-renard

The hypothalamic magnocellular neurons (MCNs) in the supraoptic and paraventricular nuclei synthesize and release vasopressin (AVP) and oxytocin (OXT), crucial for regulating renal water reabsorption and female reproductive function. MCNs also influence emotional and cognitive functions via collateral axons. Understanding their molecular regulation and diversity is essential. Recent single-nucleus RNA sequencing in rat supraoptic nucleus identified eight MCN subtypes, including major OXT and AVP-producing clusters with unique transcriptomic signatures. Cell-Chat analysis revealed communication pathways with other neuronal and glial cells, while pseudotrajectory analysis identified genes linked to transcriptional plasticity. NEUROeSTIMator and scVelo identified genes and pathways associated with neuronal activation and AVP RNA processing during water deprivation. Integrating rat data with previous RNA sequencing from other mammals showed transcriptional conservation and divergence in OXT and AVP-producing MCNs across evolution. This collective data provides a comprehensive understanding of MCN diversity, activity-related responses, and evolutionary molecular patterns in mammals.

André de Souza Mecawi
mecawi@unifesp.br
Laboratory of Molecular Neuroendocrinology
Department of Biophysics Paulista School of Medicine – Federal University of São Paulo, Brasil
https://scholar.google.com.br/citations?user=s0Cil-MAAAAJ&hl=pt-BR

It has been described that maternal forced high sodium intake during gestation and the perinatal period is capable of modulating both blood pressure and salt intake in the next generation. This early manipulation has anatomical and molecular programming effects at the renal, cerebral, and vascular levels that increase basal and induced blood pressure. In addition, the hypothalamic vasopressinergic system has also been described as a neurobiological substrate vulnerable to the effects of perinatal programming. However, the programming effects of the natriophilia proper of the perinatal period on blood pressure control and the vasopressinergic system have not yet been elucidated. Thus, our work aimed to study the effect of a sodium overload (SO) challenge on blood pressure response and renal and brain gene expression in adult offspring exposed to voluntary hypertonic sodium intake during the perinatal period (PM-NaCl group). We show that male PM-NaCl rats exhibit a more sustained increase in blood pressure after SO than controls (PM-Control). However, female PM-NaCl rats did not show a programmer effect on the blood pressure response. Also, the relative expression of heteronuclear vasopressin (AVP hnRNA) and AVP along the supraoptic nucleus was not changed after SO in PM-NaCl, in contrast to the increase observed in PM-Controls. At renal level, male PM-NaCl rats also showed a reduced number of glomeruli, decreased expression of transient receptor potential vanilloid type 1 (TRPV1), and increased expression of angiotensinergic type 1 receptor (At1a) without changes in vasopressinergic 2 receptor (V2) in the kidney cortex. The data indicate that the availability of a rich source of sodium during the perinatal period induces a long-term effect modifying renal, cardiovascular, and neuroendocrine responses implicated in the control of hydroelectrolyte homeostasis.

Andrea Godino
agodino@immf.uncor.edu
Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Friuli 2434, Córdoba 5016, Argentina Facultad de Psicología, Universidad Nacional de Córdoba, Boulevard de la Reforma & Enf. Gordillo Gómez, Córdoba 5000, Argentina
https://institutoferreyra.org/andrea-godino/