Food availability in nature is often irregular, and famine is commonplace. Increased motivation to engage in ingestive behaviors increases the chance of survival, providing additional potential opportunities for reproduction. Because of the advantages conferred by entraining ingestive behavior to environmental conditions, neuroendocrine mechanisms regulating the motivation to acquire and ingest food have evolved to be responsive to exogenous (i.e., food stored for future consumption) and endogenous (i.e., body fat stores) fuel availability. Motivated behaviors like eating occur in two phases. The appetitive phase brings animals into contact with food (e.g., foraging, food hoarding), and the more reflexive consummatory phase results in ingestion (e.g., chewing, swallowing). Quantifiable appetitive behaviors are part of the natural ingestive behavioral repertoire of species such as hamsters and humans. This review summarizes current knowledge about neuroendocrine regulators of ingestive behavior, with an emphasis appetitive behavior. We will discuss hormonal regulators of appetitive ingestive behaviors, including the orexigenic hormone ghrelin, which potently stimulates foraging and food hoarding in Siberian hamsters. This section includes a discussion of the hormone leptin, its relation to endogenous fat stores, and its role in food deprivation-induced increases in appetitive ingestive behaviors. Next, we discuss how hormonal regulators interact with neurotransmitters involved in the regulation of ingestive behaviors, such as neuropeptide Y (NPY), agouti-related protein (AgRP) and α-melanocyte stimulating hormone (α-MSH), to regulate ingestive behavior. Finally, we discuss the potential impact that perinatal nutrient availability can have on the neuroendocrine regulation of ingestive behavior. Understanding the hormonal mechanisms that connect metabolic fuel availability to central appetite regulatory circuits should provide a better understanding of the neuroendocrine regulation of the motivation to engage in ingestive behavior.
Whether from a fall, sports concussion, or even combat injury, there is a critical need to identify when an individual is able to return to play or work following traumatic brain injury (TBI). Electroencephalogram (EEG) and local field potentials (LFP) represent potential tools to monitor circuit-level abnormalities related to learning and memory: specifically, theta oscillations can be readily observed and play a critical role in cognition. Following moderate traumatic brain injury in the rat, lasting changes in theta oscillations coincide with deficits in spatial learning. We hypothesized, therefore, that theta oscillations can be used as an objective biomarker of recovery, with a return of oscillatory activity corresponding with improved spatial learning. In the current study, LFP were recorded from dorsal hippocampus and anterior cingulate in awake, behaving adult Sprague Dawley rats in both a novel environment on post-injury days 3 and 7, and Barnes maze spatial navigation on post-injury days 8–11. Theta oscillations, as measured by power, theta-delta ratio, peak theta frequency, and phase coherence, were significantly altered on day 3, but had largely recovered by day 7 post-injury. Injured rats had a mild behavioral phenotype and were not different from shams on the Barnes maze, as measured by escape latency. Injured rats did use suboptimal search strategies. Combined with our previous findings that demonstrated a correlation between persistent alterations in theta oscillations and spatial learning deficits, these new data suggest that neural oscillations, and particularly theta oscillations, have potential as a biomarker to monitor recovery of brain function following TBI. Specifically, we now demonstrate that oscillations are depressed following injury, but as oscillations recover, so does behavior.
SummaryFocal epilepsies represent approximately half of all diagnoses, and more than one‐third of these patients are refractory to pharmacologic treatment. Although resection can result in seizure freedom, many patients do not meet surgical criteria, as seizures may be multifocal in origin or have a focus in an eloquent region of the brain. For these individuals, several U.S. Food and Drug Administration (FDA)–approved electrical stimulation paradigms serve as alternative options, including vagus nerve stimulation, responsive neurostimulation, and stimulation of the anterior nucleus of the thalamus. All of these are safe, flexible, and lead to progressive seizure control over time when used as an adjunctive therapy to antiepileptic drugs. Focal epilepsies frequently involve significant comorbidities such as cognitive decline. Similar to antiepilepsy medications and surgical resection, current stimulation targets and parameters have yet to address cognitive impairments directly, with patients reporting persistent comorbidities associated with focal epilepsy despite a significant reduction in the number of their seizures. Although low‐frequency theta oscillations of the septohippocampal network are critical for modulating cellular activity and, in turn, cognitive processing, the coordination of neural excitability is also imperative for preventing seizures. In this review, we summarize current FDA‐approved electrical stimulation paradigms and propose that theta oscillations of the medial septal nucleus represent a novel neuromodulation target for concurrent seizure reduction and cognitive improvement in epilepsy. Ultimately, further advancements in clinical neurostimulation strategies will allow for the efficient treatment of both seizures and comorbidities, thereby improving overall quality of life for patients with epilepsy.
Over one-third of patients with temporal lobe epilepsy are refractory to medication. In addition, anti-epileptic drugs often exacerbate cognitive comorbidities. Neuromodulation is an FDA treatment for refractory epilepsy, but patients often wait >20 years for a surgical referral for resection or neuromodulation. Using a rodent model, we test the hypothesis that 2 weeks of theta stimulation of the medial septum acutely following exposure to pilocarpine will alter the course of epileptogenesis resulting in persistent behavioral improvements. Electrodes were implanted in the medial septum, dorsal and ventral hippocampus, and the pre-frontal cortex of pilocarpine-treated rats. Rats received 30 min/day of 7.7 Hz or theta burst frequency on days 4–16 post-pilocarpine, prior to the development of spontaneous seizures. Seizure threshold, spikes, and oscillatory activity, as well as spatial and object-based learning, were assessed in the weeks following stimulation. Non-stimulated pilocarpine animals exhibited significantly decreased seizure threshold, increased spikes, and cognitive impairments as compared to vehicle controls. Furthermore, decreased ventral hippocampal power (6–10 Hz) correlated with both the development of spikes and impaired cognition. Measures of spikes, seizure threshold, and cognitive performance in both acute 7.7 Hz and theta burst stimulated animals were statistically similar to vehicle controls when tested during the chronic phase of epilepsy, weeks after stimulation was terminated. These data indicate that modulation of the septohippocampal circuit early after pilocarpine treatment alters the progression of epileptic activity, resulting in elevated seizure thresholds, fewer spikes, and improved cognitive outcome. Results from this study support that septal theta stimulation has the potential to serve in combination or as an alternative to high frequency thalamic stimulation in refractory cases and that further research into early intervention is critical.
Multiple Sclerosis (MS) is an immune-mediated disease that results in major locomotor deficits. However, recent studies have revealed that fatigue, slow processing speed, and memory impairment are the top variables impacting employment status for MS patients. These suggest that cognitive effects may have a greater impact on productivity, lifestyle, and quality of life than do disease-related motor deficits. However, these debilitating non-locomotive effects have been largely overlooked in rodent models of the disease, such as experimental autoimmune encephalomyelitis (EAE). We hypothesized that murine EAE can also be used to assess non-locomotive dysfunctions (mood, sociability, muscle strength, and balance), as well as potential biases in these dysfunctions due to sex and/or strain. We actively immunized male and female C57BL/6 (B6) and SJL mice for EAE and evaluated their performance on the Deacon's weight grip test, Kondziela's inverted screen test, Hall's rope grip test, manual von Frey test for somatic nociception, and a three-chamber social preference paradigm. We hypothesized that EAE progression is associated with changes in muscle strength, balance, pain, and sociability and that these variations are linked to sex and/or strain. Our results indicate that strain but not sex influenced differences in muscle strength and balance during EAE, and both sex and strain have an impact on mechanical nociception, regardless of EAE disease status. Furthermore, both sex and strain had complex effects on differences in sociability. In conclusion, testing these additional modalities during EAE helps to unveil other signs and symptoms that could be used to determine the efficacy of a drug or treatment in the modulation of a MS-like behavior.
Obesity is an epidemic of growing concern. Much research has focused on the roles of hypothalamic feeding peptides in energy balance and how these are affected by gestational programming, the impact of the intrauterine environment on adult physiology. Gestational programming may also affect the mesolimbocortical pathway, which projects from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex in the brain and comprises a general reward system that reinforces natural behaviors such as eating, drinking, and sexual activity. Since low birth weight (LBW) humans tend to exhibit both obesity and a propensity toward addiction, we hypothesized that lack of maternal nutrition may cause baseline changes in dopaminergic activity that lead to perturbations in ingestive behavior. We utilized a traditional rat model of intrauterine growth restriction by placing dams on a 50% food‐restricted diet during the latter half of pregnancy. Offspring had significantly lower birth weights (5.6±0.08g vs. 6.5±0.06g, p<0.01) and significantly higher tyrosine hydroxylase (TH) immunoreactivity in the VTA than controls (159±19 vs. 454±88 A.U., p<0.05), suggesting that they would be more sensitive to rewarding stimuli. Therefore, we examined sucrose consumption in these animals over a 24 hour period and in a limited access paradigm where animals received 10% sucrose for 90 minute intervals. LBW offspring consumed significantly more (29±2ml vs. 23±1ml, p<0.05) when given limited access to sucrose. This suggests that LBW offspring increase ingestive behaviors when given limited access to substances with rewarding properties. Consequently, the dopaminergic reward system deserves closer examination to determine its role in LBW‐related obesity. Grant Funding Source: Supported by APS UGSRF Fellowship
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