Ventral hippocampus-lateral septum circuitry promotes foraging-related memory.

Remembering the location of a food or water source is essential for survival. Here, we reveal that spatial memory for food location is reflected in ventral hippocampus (HPCv) neuron activity and is impaired by HPCv lesion. HPCv mediation of foraging-related memory involves communication to the lateral septum (LS), as either reversible or chronic disconnection of HPCv-to-LS signaling impairs spatial memory retention for food or water location. This neural pathway selectively encodes appetitive spatial memory, as HPCv-LS disconnection does not affect spatial memory for escape location in a negative reinforcement procedure, food intake, or social and olfactory-based appetitive learning. Neural pathway tracing and functional mapping analyses reveal that LS neurons recruited during the appetitive spatial memory procedure are primarily GABAergic neurons that project to the lateral hypothalamus. Collective results emphasize that the neural substrates controlling spatial memory are outcome specific based on reinforcer modality.

Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats.

Oxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin's anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and sucrose reward value encoding following a motivational shift (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of sucrose reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin's effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA.

Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve.

Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the control of feeding behavior and metabolism [1]. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including affective motivational behaviors and hippocampus (HPC)-dependent memory [2-5]. VANs, located in nodose ganglia, express receptors for various gut-derived peptide signals; however, the function of these receptors with regard to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (GHSR) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNAi-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPC-dependent contextual episodic memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or general activity levels. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory.

Ghrelin and Orexin Interact to Increase Meal Size Through a Descending Hippocampus to Hindbrain Signaling Pathway.

BACKGROUND: Memory and cognitive processes influence the amount of food consumed during a meal, yet the neurobiological mechanisms mediating these effects are poorly understood. The hippocampus (HPC) has recently emerged as a brain region that integrates feeding-relevant biological signals with learning and memory processes to regulate feeding. We investigated whether the gut-derived hormone ghrelin acts in the ventral HPC (vHPC) to increase meal size through interactions with gut-derived satiation signaling. METHODS: Interactions between vHPC ghrelin signaling, gut-derived satiation signaling, feeding, and interoceptive discrimination learning were assessed via rodent behavioral neuropharmacological approaches. Downstream neural pathways were identified using transsynaptic virus-based tracing strategies. RESULTS: vHPC ghrelin signaling counteracted the food intake-reducing effects produced by various peripheral biological satiation signals, including cholecystokinin, exendin-4 (a glucagon-like peptide-1 receptor agonist), amylin, and mechanical distension of the stomach. Furthermore, vHPC ghrelin signaling produced interoceptive cues that generalized to a perceived state of energy deficit, thereby providing a potential mechanism for the attenuation of satiation processing. Neuroanatomical tracing identified a multiorder connection from vHPC neurons to lateral hypothalamic area orexin (hypocretin)-producing neurons that project to the laterodorsal tegmental nucleus in the hindbrain. Lastly, vHPC ghrelin signaling increased spontaneous meal size via downstream orexin receptor signaling in the laterodorsal tegmental nucleus. CONCLUSIONS: vHPC ghrelin signaling increases meal size by counteracting the efficacy of various gut-derived satiation signals. These effects occur via downstream orexin signaling to the hindbrain laterodorsal tegmental nucleus, thereby highlighting a novel hippocampus-hypothalamus-hindbrain pathway regulating meal size control.

Sex Differences and Estrous Influences on Oxytocin Control of Food Intake.

Central oxytocin potently reduces food intake and is being pursued as a clinical treatment for obesity. While sexually dimorphic effects have been described for the effects of oxytocin on several behavioral outcomes, the role of sex in central oxytocin modulation of feeding behavior is poorly understood. Here we investigated the effects of sex, estrous cycle stage, and female sex hormones (estrogen, progesterone) on central oxytocin-mediated reduction of food intake in rats. Results show that while intracerebroventricular (ICV) oxytocin potently reduces chow intake in both male and female rats, these effects were more pronounced in males than in females. We next examined whether estrous cycle stage affects oxytocin's food intake-reducing effects in females. Results show that ICV oxytocin administration significantly reduces food intake during all estrous cycle stages except proestrous, suggesting that female sex hormones may modulate the feeding effects of oxytocin. Indeed, additional results reveal that estrogen, but not progesterone replacement, in ovariectomized rats abolishes oxytocin-mediated reductions in chow intake. Lastly, oxytocin receptor mRNA (Oxtr) quantification (via quantitative PCR) and anatomical localization (via fluorescent in situ hybridization) in previously established sites of action for oxytocin control of food intake revealed comparable Oxtr expression between male and female rats, suggesting that observed sex and estrous differences may be based on variations in ligand availability and/or binding. Overall, these data show that estrogen reduces the effectiveness of central oxytocin to inhibit food intake, suggesting that sex hormones and estrous cycle should be considered in clinical investigations of oxytocin for obesity treatment.

Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone.

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Regulation of Memory Function by Feeding-Relevant Biological Systems: Following the Breadcrumbs to the Hippocampus.

The hippocampus (HPC) controls fundamental learning and memory processes, including memory for visuospatial navigation (spatial memory) and flexible memory for facts and autobiographical events (declarative memory). Emerging evidence reveals that hippocampal-dependent memory function is regulated by various peripheral biological systems that are traditionally known for their roles in appetite and body weight regulation. Here, we argue that these effects are consistent with a framework that it is evolutionarily advantageous to encode and recall critical features surrounding feeding behavior, including the spatial location of a food source, social factors, post-absorptive processing, and other episodic elements of a meal. We review evidence that gut-to-brain communication from the vagus nerve and from feeding-relevant endocrine systems, including ghrelin, insulin, leptin, and glucagon-like peptide-1 (GLP-1), promote hippocampal-dependent spatial and declarative memory via neurotrophic and neurogenic mechanisms. The collective literature reviewed herein supports a model in which various stages of feeding behavior and hippocampal-dependent memory function are closely linked.

Gut vagal sensory signaling regulates hippocampus function through multi-order pathways.

The vagus nerve is the primary means of neural communication between the gastrointestinal (GI) tract and the brain. Vagally mediated GI signals activate the hippocampus (HPC), a brain region classically linked with memory function. However, the endogenous relevance of GI-derived vagal HPC communication is unknown. Here we utilize a saporin (SAP)-based lesioning procedure to reveal that selective GI vagal sensory/afferent ablation in rats impairs HPC-dependent episodic and spatial memory, effects associated with reduced HPC neurotrophic and neurogenesis markers. To determine the neural pathways connecting the gut to the HPC, we utilize monosynaptic and multisynaptic virus-based tracing methods to identify the medial septum as a relay connecting the medial nucleus tractus solitarius (where GI vagal afferents synapse) to dorsal HPC glutamatergic neurons. We conclude that endogenous GI-derived vagal sensory signaling promotes HPC-dependent memory function via a multi-order brainstem-septal pathway, thereby identifying a previously unknown role for the gut-brain axis in memory control.

Control of Feeding Behavior by Cerebral Ventricular Volume Transmission of Melanin-Concentrating Hormone.

Classical mechanisms through which brain-derived molecules influence behavior include neuronal synaptic communication and neuroendocrine signaling. Here we provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving cerebroventricular volume transmission of the neuropeptide melanin-concentrating hormone (MCH). Results reveal that the cerebral ventricles receive input from approximately one-third of MCH-producing neurons. Moreover, MCH cerebrospinal fluid (CSF) levels increase prior to nocturnal feeding and following chemogenetic activation of MCH-producing neurons. Utilizing a dual viral vector approach, additional results reveal that selective activation of putative CSF-projecting MCH neurons increases food intake. In contrast, food intake was reduced following immunosequestration of MCH endogenously present in CSF, indicating that neuropeptide transmission through the cerebral ventricles is a physiologically relevant signaling pathway for energy balance control. Collectively these results suggest that neural-CSF volume transmission signaling may be a common neurobiological mechanism for the control of fundamental behaviors.

Hippocampus ghrelin receptor signaling promotes socially-mediated learned food preference.

Social cues are potent regulators of feeding behavior, yet the neurobiological mechanisms through which social cues influence food intake are poorly understood. Here we investigate the hypothesis that the appetite-promoting gut-derived hormone, ghrelin, signals in the hippocampus to promote learned social aspects of feeding behavior. We utilized a procedure known as 'social transmission of food preference' (STFP) in which rats ('Observers') experience a social interaction with another rat ('Demonstrators') that recently consumed flavored/scented chow. STFP learning in Observer rats is indicated by a significant preference for the Demonstrator paired flavor of chow vs. a novel unpaired flavor of chow in a subsequent consumption choice test. Our results show that relative to vehicle treatment, ghrelin targeted to the ventral CA1 subregion of the hippocampus (vHP) enhanced STFP learning in rats. Additionally, STFP was impaired following peripheral injections of l-cysteine that reduce circulating ghrelin levels, suggesting that vHP ghrelin-mediated effects on STFP require peripheral ghrelin release. Finally, the endogenous relevance of vHP ghrelin receptor (GHSR-1A) signaling in STFP is supported by our data showing that STFP learning was eliminated following targeted viral vector RNA interference-mediated knockdown of vHP GHSR-1A mRNA. Control experiments indicate that vHP ghrelin-mediated STFP effects are not secondary to altered social exploration and food intake, nor to altered food preference learning based on nonsocial olfactory cues. Overall these data reveal a novel neurobiological system that promotes conditioned, social aspects of feeding behavior.

Ruptura del septum ventricular como complicación de un evento coronario agudo / Ventricular septal rupture complicating acute myocardial infarction

Resumen La ruptura del septum ventricular (RSV) es una complicación mecánica infrecuente del infarto agudo de miocardio (IAM). Los principales factores de riesgo descritos son la edad avanzada, el género femenino, un primer episodio de IAM y la presencia de enfermedad coronaria. Se sospecha de esta patología cuando clínicamente se evidencia un deterioro inexplicable del estado hemodinámico posterior al infarto. Los estudios imagenológicos (ecocardiograma y Doppler color) ayudan a confirmar el diagnóstico de RSV. Respecto al manejo, la corrección quirúrgica continúa siendo el pilar del tratamiento, ya que posee menor mortalidad en comparación con el abordaje médico no quirúrgico. Se presentan dos casos de ruptura del septum ventricular; el primero corresponde a una paciente femenina adulta mayor, con múltiples comorbilidades, quien desarrolló un síndrome coronario agudo tipo infarto agudo de miocardio con elevación del segmento ST a nivel anteroseptal. Se le realizó angioplastia primaria con evidencia de ruptura del septum ventricular, que fue corregida mediante cirugía de forma temprana. Pasadas veinticuatro horas, presentó ruptura de la pared libre del ventrículo izquierdo, hecho que precipitó su deceso. El segundo caso es una paciente femenina adulta mayor, quien presentó síndrome coronario agudo tipo infarto agudo de miocardio sin elevación del ST en cara lateral. Siete días después se documentó la existencia de la ruptura del septum ventricular, la cual fue corregida de manera tardía, en el día octavo, sin complicaciones asociadas.

Abstract Ventricular septal rupture (VSR) is a rare mechanical complication of acute myocardial infarction (AMI). The main risk factors described are advanced age, female gender, a first episode of AMI and presence of coronary disease. There is suspicion for this condition when clinical evidence shows unexplained deterioration of hemodynamic status following infarction. Imaging studies (echocardiogram and colour Doppler) help confirm the diagnosis of ventricular septal rupture. Regarding management, surgical correction continues to be the mainstay of treatment, as it poses lower mortality in comparison to nonsurgical medical approach. Two cases of VSR are presented, the first one is a female adult patient with multiple comorbidities who developed an acute coronary syndrome of a acute myocardial infarction with an anteroseptal ST segment elevation. Primary angioplasty was performed that evidenced ventricular septal rupture, which was surgically corrected at an early stage. After 24 hours, patient showed left ventricular free wall rupture, which precipitated her death. Second case is a female old patient who presented acute acute coronary syndrome of a acute myocardial infarction without lateral ST segment elevation. Seven days later a ventricular septal rupture was documented, which was corrected at a later stage on the eighth day without associated complications.

Ghrelin: A link between memory and ingestive behavior.

Feeding is a highly complex behavior that is influenced by learned associations between external and internal cues. The type of excessive feeding behavior contributing to obesity onset and metabolic deficit may be based, in part, on conditioned appetitive and ingestive behaviors that occur in response to environmental and/or interoceptive cues associated with palatable food. Therefore, there is a critical need to understand the neurobiology underlying learned aspects of feeding behavior. The stomach-derived "hunger" hormone, ghrelin, stimulates appetite and food intake and may function as an important biological substrate linking mnemonic processes with feeding control. The current review highlights data supporting a role for ghrelin in mediating the cognitive and neurobiological mechanisms that underlie conditioned feeding behavior. We discuss the role of learning and memory on food intake control (with a particular focus on hippocampal-dependent memory processes) and provide an overview of conditioned cephalic endocrine responses. A neurobiological framework is provided through which conditioned cephalic ghrelin secretion signals in neurons in the hippocampus, which then engage orexigenic neural circuitry in the lateral hypothalamus to express learned feeding behavior.

Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways.

Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling.