Sweet orosensation induces Arc expression in dorsal hippocampal CA1 neurons in an experience-dependent manner.

There is limited knowledge regarding how the brain controls the timing of meals. Similarly, there is a large gap in our understanding of how top-down cognitive processes, such as memory influence energy intake. We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit meal onset during the postprandial period. In support, we showed previously that reversible inactivation of these neurons during the period following a sucrose meal accelerates the onset of the next meal. If dHC neurons form a memory of a meal, then consumption should induce synaptic plasticity in dHC neurons. To test this, we determined (1) whether a sucrose meal increases the expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC CA1 neurons, (2) whether previous experience with sucrose influences sucrose-induced Arc expression, and (3) whether the orosensory stimulation produced by the noncaloric sweetener saccharin is sufficient to induce Arc expression. Male Sprague-Dawley rats were trained to consume a sweetened solution at a scheduled time daily. On the experimental day, they were given a solution for 7 min, euthanized, and then fluorescence in situ hybridization procedures were used to measure meal-induced Arc mRNA. Compared to caged control rats, Arc expression was significantly higher in rats that consumed sucrose or saccharin. Interestingly, rats given additional experience with sucrose had less Arc expression than rats with less sucrose experience, even though both groups consumed similar amounts on the experimental day. Thus, this study is the first to suggest that orosensory stimulation produced by consuming a sweetened solution and possibly the hedonic value of that sweet stimulation induces synaptic plasticity in dHC CA1 neurons in an experience-dependent manner. Collectively, these findings are consistent with our hypothesis that dHC neurons form a memory of a meal.

Early life inflammatory pain induces long-lasting deficits in hippocampal-dependent spatial memory in male and female rats.

The present experiment tested the hypothesis that neonatal injury disrupts adult hippocampal functioning and that normal aging or chronic stress during adulthood, which are known to have a negative impact on hippocampal function, exacerbate these effects. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and their memory was tested in the hippocampal-dependent spatial water maze in adulthood and again in middle age. We found that neonatal injury impaired hippocampal-dependent memory in adulthood, that the effects of injury on memory were more pronounced in middle-aged male rats, and that chronic stress accelerated the onset of these memory deficits. Neonatal injury also decreased glucocorticoid receptor mRNA in the dorsal CA1 area of middle-aged rats, a brain region critical for spatial memory. Morphine administration at the time of injury completely reversed injury-induced memory deficits, but neonatal morphine treatments in the absence of injury produced significant memory impairments in adulthood. Collectively, these findings are consistent with our hypothesis that neonatal injury produces long-lasting disruption in adult hippocampal functioning.

Remembering to eat: hippocampal regulation of meal onset.

A wide variety of species, including vertebrate and invertebrates, consume food in bouts (i.e., meals). Decades of research suggest that different mechanisms regulate meal initiation (when to start eating) versus meal termination (how much to eat in a meal, also known as satiety). There is a very limited understanding of the mechanisms that regulate meal onset and the duration of the postprandial intermeal interval (ppIMI). In the present review, we examine issues involved in measuring meal onset and some of the limited available evidence regarding how it is regulated. Then, we describe our recent work indicating that dorsal hippocampal neurons inhibit meal onset during the ppIMI and describe the processes that may be involved in this. We also synthesize recent evidence, including evidence from our laboratory, suggesting that overeating impairs hippocampal functioning and that impaired hippocampal functioning, in turn, contributes to the development and/or maintenance of diet-induced obesity. Finally, we identify critical questions and challenges for future research investigating neural controls of meal onset.

Hippocampal neurons inhibit meal onset.

There is extensive research regarding the neural mechanisms involved in satiety and meal termination; in contrast, there is very limited understanding of how meal onset is regulated. On the basis of several converging lines of evidence, we hypothesized that hippocampal neurons form a memory of a meal and inhibit meal onset during the postprandial period. As a first step, we tested whether reversible inactivation of the hippocampus with muscimol infusions after the end of one meal would accelerate the onset of the next meal. To test this, adult male Sprague-Dawley rats (N = 23) were implanted with a cannula aimed at the right or left dorsal hippocampus and then trained to consume a 32% sucrose solution at a scheduled time daily. On the experimental day, hippocampal neuronal activity was temporarily disrupted during the postprandial period by infusing muscimol (0.5 µg/µl; 1 µl) 5 min after the rats stopped consuming the sucrose solution. Compared to vehicle infusions, muscimol infusions significantly decreased the latency to start the postinfusion meal and increased the size of the postinfusion meal. In addition, muscimol disrupted the relationship between the size of a meal and length of the following postprandial period. These effects of muscimol on meal onset were not due to an effect on the speed of consumption. Collectively, these findings are consistent with the hypothesis that hippocampal neurons suppress meal initiation during the postprandial period. Given that overeating can impair hippocampal function, these findings suggest that impaired hippocampal functioning is a cause and consequence of overeating and obesity.

A long-term obesogenic high-fat diet in mice partially dampens the anti-frailty benefits of late-life intermittent fasting.

The global obesity pandemic coupled with ever-growing life expectancies equates to hundreds of millions of individuals with potentially longer but not healthier lives. Aging is one of the risk factors for numerous maladies such as metabolic disorder and frailty, which are exacerbated under obesity. Thus, therapeutic approaches that address obesity to ultimately improve affected individuals' quality of life and extend their lifespan are needed. We previously reported that the every other day (EOD) fasting initiated late-life improved metabolic, musculoskeletal, and cognitive endpoints in standard rodent diet-fed mice. In the present study, using the same dietary intervention methodology, we tested if 2.5 months of EOD fasting could improve metabolic, physiological, and cognitive endpoints in mice after an 18 month obesogenic high-fat diet (HFD). The positive effects of EOD fasting were generally consistent across the endpoints; EOD fasting decreased total body mass, maintained more %lean mass, improved glucose tolerance and utilization, and improved neuromuscular function. In contrast to our previous study, grip strength, hippocampal-dependent memory, and renal hydrogen sulfide (H2S) production were not improved by the HFD EOD fasting. Thus, efficacy for late-life initiated intermittent fasting to improve specific frailty markers may be partially dependent on nutritional compositions of the diet.

Peripubertal Bisphenol A Exposure Imparts Detrimental Age-Related Changes in Body Composition, Cognition, and Hydrogen Sulfide Production Capacities.

Aims: Peripubertal endocrine disruption has immediate and lifelong consequences on health, cognition, and lifespan. Disruption comes from dietary, environmental, and pharmaceutical sources. The plasticizer Bisphenol A (BPA) is one such endocrine disrupting chemical. However, it is unclear whether peripubertal BPA exposure incites long-lasting physiological, neuro-cognitive, and/or longevity-related metabolic impairments. Catabolism of cysteine via transsulfuration enzymes produces hydrogen sulfide (H2S), a redox-modulating gasotransmitter causative to endocrine and metabolic homeostasis and improved cognitive function with age. As thyroid hormone (TH) regulates hepatic H2S production and BPA is a TH receptor antagonist, we hypothesized that BPA exposure during peripubertal development impairs metabolic and neuro-cognitive/behavioral endpoints in aged mice, in part, due to altered peripheral and/or localized H2S production and redox status. Results: To test this, male C57BL/6J mice at 5 weeks of age were orally exposed daily for 5 weeks to 250 µg BPA/kg, defined as low dose group (LD BPA), or 250 mg BPA/kg, defined as high dose group (HD BPA). Both LD and HD BPA exposure decreased lean mass and increased fat mass accompanied by decreased serum total TH at advanced ages. In addition, LD BPA had an anxiogenic effect whereas HD BPA caused cognitive deficits. Notably, HD BPA disrupted tissue-specific H2S production capacities and/or protein persulfidation, with the former negatively correlated with memory deficits and oxidative stress. Innovation and Conclusion: These findings provide a potential mechanism of action for acute and long-term health impacts of BPA-induced peripubertal endocrine disruption and bolster the need for improved monitoring and limitation of adolescent BPA exposure.

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner.

Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H2S) and that renal H2S production declines with age, we tested the effects of EOD fasting on renal H2S production capacity and its connection to frailty in males. EOD fasting boosted renal H2S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H2S production capacity may modulate the effects of late-life EOD fasting on frailty.

Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine γ-lyase-dependent manner.

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

Sex-dependent effects of early life inflammatory pain on sucrose intake and sucrose-associated hippocampal Arc expression in adult rats.

We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit the initiation of the next meal and the amount ingested during that meal. In support, we showed previously that (1) consuming a sucrose meal induces expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC neurons and (2) reversible inactivation of these neurons immediately following a sucrose meal accelerates the onset of the next meal and increases the size of that meal. These data suggest that hippocampal-dependent memory inhibits intake; therefore, the following experiments were conducted to determine whether hippocampal-dependent memory impairments are associated with increased intake. We reported recently that one episode of early life inflammatory pain impairs dHC-dependent memory in adult rats. The present study determined whether neonatal inflammatory pain also increases sucrose intake and attenuates sucrose-associated Arc expression. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and sucrose intake and sucrose-associated dHC Arc expression were measured in adulthood. Neonatal inflammatory pain increased sucrose intake in adult female and male rats, decreased sucrose-associated dHC Arc expression in female rats, and tended to have a similar effect on Arc expression in male rats. Neonatal inflammatory pain significantly decreased the interval between two sucrose meals in female but not in male rats. Morphine administration at the time of insult attenuated the effects of injury on sucrose intake. Collectively, these findings indicate that one brief episode of inflammatory pain on the day of birth has a long long-lasting, sex-dependent impact on intake of a palatable food in adulthood.

An analysis of nicotine conditioned place conditioning in early postweanling and adolescent rats neonatally treated with quinpirole.

This study investigated nicotine place conditioning in early postweanling and adolescent male and female rats neonatally treated with quinpirole, a dopamine D(2)/D(3) agonist. Previous research has shown that neonatal quinpirole treatment results in an increase of dopamine D(2)-like receptor sensitivity that persists throughout the animal's lifetime, relevant to psychosis. Rats were neonatally treated with quinpirole or saline from postnatal day (P)1-21, and animals were conditioned with nicotine or saline daily from P23-30 as early postweanlings or P32-39 as adolescents in a two- or three-chambered place conditioning apparatus. A drug free test was given on P31 for early postweanlings, and P40 for adolescents. Results on the two chamber apparatus revealed that nicotine increased time spent in the drug-paired context at both ages tested. Neonatal quinpirole treatment resulted in less time spent in the drug-paired context in early postweanling males and increased time spent in the drug-paired context in adolescent females conditioned with nicotine. Adolescent females neonatally treated with saline and conditioned with nicotine on the two chamber apparatus did not differ from controls. On the three-chambered apparatus, nicotine increased time spent in the drug-paired context in both ages tested, which was blocked by neonatal quinpirole in early postweanling males, but enhanced by neonatal quinpirole treatment in adolescents. These results demonstrate both age and sex differences in the effects of nicotine and point to significant differences in performance depending on the apparatus used. Additionally, neonatal quinpirole enhanced the effects of nicotine, but this is true only in adolescents and task-dependent.