Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26-56). Behavioral and metabolic assessments were performed both before and after a healthy diet intervention period beginning at early adulthood. Results revealed HPC-dependent contextual episodic memory impairments in CAF rats that persisted despite the healthy diet intervention. Given that dysregulated HPC acetylcholine (ACh) signaling is associated with memory impairments in humans and animal models, we examined protein markers of ACh tone in the dorsal HPC (HPCd) in CAF and CTL rats. Results revealed significantly lower protein levels of vesicular ACh transporter in the HPCd of CAF vs. CTL rats, indicating chronically reduced ACh tone. Using intensity-based ACh sensing fluorescent reporter (iAChSnFr) in vivo fiber photometry targeting the HPCd, we next revealed that ACh release during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Neuropharmacological results showed that alpha 7 nicotinic ACh receptor agonist infusion in the HPCd during training rescued memory deficits in CAF rats. Overall, these findings reveal a functional connection linking early life WD intake with long-lasting dysregulation of HPC ACh signaling, thereby identifying an underlying mechanism for WD-associated memory impairments.

Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats.

Early life Western diet (WD) consumption leads to impaired memory function, particularly for processes mediated by the hippocampus. However, the precise critical developmental window(s) during which WD exposure negatively impacts hippocampal function are unknown. Here, we exposed male and female rats to a WD model involving free access to a variety of high-fat and/or high-sugar food and drink items during either the early-adolescent period (postnatal days [PN] 26-41; WD-EA) or late-adolescent period (PN 41-56; WD-LA). Control (CTL) rats were given healthy standard chow throughout both periods. To evaluate long-lasting memory capacity well beyond the early life WD exposure periods, we performed behavioral assessments after both a short (4 weeks for WD-EA, 2 weeks for WD-LA) and long (12 weeks for WD-EA, 10 weeks for WD-LA) period of healthy diet intervention. Results revealed no differences in body weight or body composition between diet groups, regardless of sex. Following the shorter period of healthy diet intervention, both male and female WD-EA and WD-LA rats showed deficits in hippocampal-dependent memory compared to CTL rats. Following the longer healthy diet intervention period, memory impairments persisted in male WD-EA but not WD-LA rats. In contrast, in female rats the longer healthy diet intervention reversed the initial memory impairments in both WD-EA and WD-LA rats. Collectively, these findings reveal that early-adolescence is a critical period of long-lasting hippocampal vulnerability to dietary insults in male but not female rats, thus highlighting developmental- and sex-specific effects mediating the relationship between the early life nutritional environment and long-term cognitive health.

Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats.

Early life Western diet (WD) consumption leads to impaired memory function, particularly for processes mediated by the hippocampus. However, the precise critical developmental window(s) during which WD exposure negatively impacts hippocampal function are unknown. Here, we exposed male and female rats to a WD model involving free access to a variety of high-fat and/or high-sugar food and drink items during either the early-adolescent period (postnatal days [PN] 26-41; WD-EA) or late-adolescent period (PN 41-56; WD-LA). Control (CTL) rats were given healthy standard chow throughout both periods. To evaluate long-lasting memory capacity well beyond the early life WD exposure periods, we performed behavioral assessments after both a short (4 weeks for WD-EA, 2 weeks for WD-LA) and long (12 weeks for WD-EA, 10 weeks for WD-LA) period of healthy diet intervention. Results revealed no differences in body weight or body composition between diet groups, regardless of sex. Following the shorter period of healthy diet intervention, both male and female WD-EA and WD-LA rats showed deficits in hippocampal-dependent memory compared to CTL rats. Following the longer healthy diet intervention period, memory impairments persisted in male WD-EA but not WD-LA rats. In contrast, in female rats the longer healthy diet intervention reversed the initial memory impairments in both WD-EA and WD-LA rats. Collectively, these findings reveal that early-adolescence is a critical period of long-lasting hippocampal vulnerability to dietary insults in male but not female rats, thus highlighting developmental- and sex-specific effects mediating the relationship between the early life nutritional environment and long-term cognitive health.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during development yields long-lasting memory impairments, yet the underlying neurobiological mechanisms remain elusive. Here we developed an early life WD rodent model to evaluate whether dysregulated hippocampus (HPC) acetylcholine (ACh) signaling, a pathology associated with memory impairment in human dementia, is causally-related to WD-induced cognitive impairment. Rats received a cafeteria-style WD (access to various high-fat/high-sugar foods; CAF) or healthy chow (CTL) during the juvenile and adolescent periods (postnatal days 26-56). Behavioral, metabolic, and microbiome assessments were performed both before and after a 30-day healthy diet intervention beginning at early adulthood. Results revealed CAF-induced HPC-dependent contextual episodic memory impairments that persisted despite healthy diet intervention, whereas CAF was not associated with long-term changes in body weight, body composition, glucose tolerance, anxiety-like behavior, or gut microbiome. HPC immunoblot analyses after the healthy diet intervention identified reduced levels of vesicular ACh transporter in CAF vs. CTL rats, indicative of chronically reduced HPC ACh tone. To determine whether these changes were functionally related to memory impairments, we evaluated temporal HPC ACh binding via ACh-sensing fluorescent reporter in vivo fiber photometry during memory testing, as well as whether the memory impairments could be rescued pharmacologically. Results revealed dynamic HPC ACh binding during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Further, HPC alpha-7 nicotinic receptor agonist infusion during consolidation rescued memory deficits in CAF rats. Overall, these findings identify dysregulated HPC ACh signaling as a mechanism underlying early life WD-associated memory impairments.

Early-life influences of low-calorie sweetener consumption on sugar taste.

Children and adolescents are the highest consumers of added sugars, particularly from sugar-sweetened beverages (SSB). Regular consumption of SSB early in life induces a variety of negative consequences on health that can last into adulthood. Low-calorie sweeteners (LCS) are increasingly used as an alternative to added sugars because they provide a sweet sensation without adding calories to the diet. However, the long-term effects of early-life consumption of LCS are not well understood. Considering LCS engage at least one of the same taste receptors as sugars and potentially modulate cellular mechanisms of glucose transport and metabolism, it is especially important to understand how early-life LCS consumption impacts intake of and regulatory responses to caloric sugars. In our recent study, we found that habitual intake of LCS during the juvenile-adolescence period significantly changed how rats responded to sugar later in life. Here, we review evidence that LCS and sugars are sensed via common and distinct gustatory pathways, and then discuss the implications this has for shaping sugar-associated appetitive, consummatory, and physiological responses. Ultimately, the review highlights the diverse gaps in knowledge that will be necessary to fill to understand the consequences of regular LCS consumption during important phases of development.

Early Life Low-Calorie Sweetener Consumption Impacts Energy Balance during Adulthood.

Children frequently consume beverages that are either sweetened with sugars (sugar-sweetened beverages; SSB) or low-calorie sweeteners (LCS). Here, we evaluated the effects of habitual early life consumption of either SSB or LCS on energy balance later during adulthood. Male and female rats were provided with chow, water, and a solution containing either SSB (sucrose), LCS (acesulfame potassium (ACE-K) or stevia), or control (no solution) during the juvenile and adolescent periods (postnatal days 26-70). SSB or LCS consumption was voluntary and restricted within the recommended federal daily limits. When subsequently maintained on a cafeteria-style junk food diet (CAF; various high-fat, high-sugar foods) during adulthood, ACE-K-exposed rats demonstrated reduced caloric consumption vs. the controls, which contributed to lower body weights in female, but not male, ACE-K rats. These discrepant intakes and body weight effects in male ACE-K rats are likely to be based on reduced gene expression of thermogenic indicators (UCP1, BMP8B) in brown adipose tissue. Female stevia-exposed rats did not differ from the controls in terms of caloric intake or body weight, yet they consumed more SSB during CAF exposure in adulthood. None of the SSB-exposed rats, neither male nor female, differed from the controls in terms of total adult caloric consumption or body weight measures. The collective results reveal that early life LCS consumption alters sugar preference, body weight, and gene expression for markers of thermogenesis during adulthood, with both sex- and sweetener-dependent effects.

Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region-specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats.

Mutations in the putative glutamatergic synapse scaffolding protein SAP97 are associated with the development of schizophrenia in humans. However, the role of SAP97 in synaptic regulation is unclear. Here we show that SAP97 is expressed in the dendrites of granule neurons in the dentate gyrus but not in the dendrites of other hippocampal neurons. Schizophrenia-related perturbations of SAP97 did not affect CA1 pyramidal neuron synapse function. Conversely, these perturbations produce dramatic augmentation of glutamatergic neurotransmission in granule neurons that can be attributed to a release of perisynaptic GluA1-containing AMPA receptors into the postsynaptic densities of perforant pathway synapses. Furthermore, inhibiting SAP97 function in the dentate gyrus was sufficient to impair contextual episodic memory. Together, our results identify a cell-type-specific synaptic regulatory mechanism in the dentate gyrus that, when disrupted, impairs contextual information processing in rats.

Early life Western diet-induced memory impairments and gut microbiome changes in female rats are long-lasting despite healthy dietary intervention.

OBJECTIVE: Western diet consumption during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes persist in adulthood following healthy dietary intervention is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar or both sugar and fat on metabolic outcomes, HPC function, and gut microbiota. METHODS: Adolescent female rats (PN 26) were fed a standard chow diet (CHOW), chow with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing various foods high in fat and/or sugar. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated. In a subsequent experiment, these outcomes were evaluated following a 5-week dietary intervention where CAF and SUG groups were maintained on standard chow alone. RESULTS: Both CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to the CHOW group. However, impaired peripheral glucose regulation was only observed in the SUG group. When examined following a healthy dietary intervention in a separate experiment, metabolic dysfunction was not observed in either the CAF or SUG group, whereas HPC-dependent memory impairments were observed in the CAF but not the SUG group. In both groups the composition of the gut microbiota remained distinct from CHOW rats after the dietary intervention. CONCLUSIONS: While the metabolic impairments associated with adolescent junk food diet consumption are not present in adulthood following dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.

Gut microbial taxa elevated by dietary sugar disrupt memory function.

Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Excessive consumption of sugar and other unhealthy dietary factors during early life developmental periods yields changes in the gut microbiome as well as neurocognitive impairments. However, it is unclear whether these two outcomes are functionally connected. Here we explore whether excessive early life consumption of added sugars negatively impacts memory function via the gut microbiome. Rats were given free access to a sugar-sweetened beverage (SSB) during the adolescent stage of development. Memory function and anxiety-like behavior were assessed during adulthood and gut bacterial and brain transcriptome analyses were conducted. Taxa-specific microbial enrichment experiments examined the functional relationship between sugar-induced microbiome changes and neurocognitive and brain transcriptome outcomes. Chronic early life sugar consumption impaired adult hippocampal-dependent memory function without affecting body weight or anxiety-like behavior. Adolescent SSB consumption during adolescence also altered the gut microbiome, including elevated abundance of two species in the genus Parabacteroides (P. distasonis and P. johnsonii) that were negatively correlated with hippocampal function. Transferred enrichment of these specific bacterial taxa in adolescent rats impaired hippocampal-dependent memory during adulthood. Hippocampus transcriptome analyses revealed that early life sugar consumption altered gene expression in intracellular kinase and synaptic neurotransmitter signaling pathways, whereas Parabacteroides microbial enrichment altered gene expression in pathways associated with metabolic function, neurodegenerative disease, and dopaminergic signaling. Collectively these results identify a role for microbiota "dysbiosis" in mediating the detrimental effects of early life unhealthy dietary factors on hippocampal-dependent memory function.

Western Diet Consumption During Development: Setting the Stage for Neurocognitive Dysfunction.

The dietary pattern in industrialized countries has changed substantially over the past century due to technological advances in agriculture, food processing, storage, marketing, and distribution practices. The availability of highly palatable, calorically dense foods that are shelf-stable has facilitated a food environment where overconsumption of foods that have a high percentage of calories derived from fat (particularly saturated fat) and sugar is extremely common in modern Westernized societies. In addition to being a predictor of obesity and metabolic dysfunction, consumption of a Western diet (WD) is related to poorer cognitive performance across the lifespan. In particular, WD consumption during critical early life stages of development has negative consequences on various cognitive abilities later in adulthood. This review highlights rodent model research identifying dietary, metabolic, and neurobiological mechanisms linking consumption of a WD during early life periods of development (gestation, lactation, juvenile and adolescence) with behavioral impairments in multiple cognitive domains, including anxiety-like behavior, learning and memory function, reward-motivated behavior, and social behavior. The literature supports a model in which early life WD consumption leads to long-lasting neurocognitive impairments that are largely dissociable from WD effects on obesity and metabolic dysfunction.

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.

Junk Food Exposure Disrupts Selection of Food-Seeking Actions in Rats.

There is growing evidence that repeated consumption of highly palatable, nutritionally poor "junk food" diets can produce deficits in cognition and behavioral control. We explored whether long-term junk-food diet exposure disrupts rats' ability to make adaptive choices about which foods to pursue based on (1) expected reward value (outcome devaluation test) and (2) cue-evoked reward expectations (Pavlovian-to-instrumental test). Rats were initially food restricted and trained on two distinct response-outcome contingencies (e.g., left press chocolate pellets, and right press sweetened condensed milk) and stimulus-outcome contingencies (e.g., white noise chocolate pellets, and clicker sweetened condensed milk). They were then given 6 weeks of unrestricted access to regular chow alone (controls) or chow and either 1 or 24 h access to junk food per day. Subsequent tests of decision making revealed that rats in both junk-food diet groups were impaired in selecting actions based on either expected food value or the presence of food-paired cues. These data demonstrate that chronic junk food consumption can disrupt the processes underlying adaptive control over food-seeking behavior. We suggest that the resulting dysregulation of food seeking may contribute to overeating and obesity.

Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice.

How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3-4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined.

Assessing the quality of human research protection programs to improve protection of human subjects participating in clinical trials.

INTRODUCTION: Institutions conducting research involving human subjects establish human research protection programs to ensure the rights and welfare of research participants as well as to meet ethical and regulatory requirements. It is important to determine whether human research protection programs have achieved these objectives. METHODS: The Department of Veterans Affairs has developed quality indicators and annually collected human research protection program quality indicator data from its 108 research facilities since 2010. RESULTS: Analysis of Department of Veterans Affairs human research protection program quality indicator data revealed that facilities using affiliated university institutional review boards performed as well as those using their own Department of Veterans Affairs institutional review boards and that facilities with small research programs, that is, less than 50 human research protocols, performed at least as well as those with larger research programs. These quality indicator data also provided Department of Veterans Affairs facilities with valuable information for quality improvement. Many of these quality indicators have improved in subsequent years, and none has deteriorated. Lapse rates in institutional review board continuing reviews remained high and relatively constant at above 6.0% over a 4-year period from 2010 through 2013. DISCUSSION: Future efforts should be directed at developing a set of human research protection program quality indicators truly reflecting the quality of human research protection programs that are applicable to both Department of Veterans Affairs and non-Department of Veterans Affairs institutions and determining whether high-quality human research protection programs as measured using these quality indicators translate into better human subject protections.

Nursing home-associated infections in Department of Veterans Affairs community living centers.

BACKGROUND: Little is known about factors contributing to nursing home-associated infections (NHAIs). We conducted a survey of residents in 133 Department of Veterans Affairs community living centers to determine the roles of indwelling device use, bed locations, and treatment codes on NHAIs. METHODS: A Web-based point prevalence survey of NHAIs using modified Centers for Disease Control and Prevention definitions for health care-associated infections was conducted on November 14, 2007. RESULTS: Among 10,939 residents, 575 had at least one NHAI, for a point prevalence rate of 5.3%. Urinary tract infection, skin infection, asymptomatic bacteriuria, and pneumonia were the most prevalent NHAIs. A total of 2687 residents had one or more indwelling devices; 290 of these also had an NHAI, for a prevalence of 10.8%. In contrast, the prevalence of NHAIs in residents without indwelling devices was 3.5% (P < .0001). Indwelling urinary catheters, percutaneous gastrostomy tubes, peripherally inserted central catheters, and suprapubic urinary catheters were the most commonly used devices. There were 4027 residents in designated units and 6912 residents in dispersed units. The rate of device use was 21.4% in the designated units and 26.4% in the dispersed units (P < .0001). The prevalence of NHAIs was 4.5% in the designated units and 5.7% in the dispersed units (P < .001). Rates of NHAIs and device use varied greatly among the various treatment codes; however, there was a positive correlation between the rates of NHAIs and device use. Stepwise logistic regression analysis of data from long-stay and short-stay skilled nursing care residents revealed that only the presence of an indwelling device, not length of stay or bed location, affected the rate of NHAIs. CONCLUSION: Indwelling device use, but not bed location or treatment code, was found to be associated with increased rate of NHAIs.

Prevalence of nursing home-associated infections in the Department of Veterans Affairs nursing home care units.

BACKGROUND: The Department of Veterans Affairs (VA) is the largest single provider of long-term care in the United States. The prevalence of nursing home-associated infections (NHAIs) among residents of VA nursing home care units (NHCUs) is not known. METHODS: A Web-based point prevalence survey of NHAIs using modified Centers for Disease Control and Prevention definitions for health care-associated infections was conducted in the VA's 133 NHCUs on November 9, 2005. RESULTS: From a total population of 11,475 NHCU residents, 591 had at least 1 NHAI for a point prevalence rate of 5.2%. Urinary tract infection, asymptomatic bacteriuria, pneumonia, skin infection, gastroenteritis, and soft tissue infection were most prevalent, constituting 72% of all NHAIs. A total of 2817 residents (24.5%) had 1 or more indwelling device. Of these 2817 residents with an indwelling device(s), 309 (11.0%) had 1 or more NHAI. In contrast, the prevalence of NHAIs in residents without an indwelling device was 3.3%. Indwelling urinary catheter, percutaneous gastrostomy tube, intravenous peripheral line, peripherally inserted central catheter, and suprapubic urinary catheter were most common, accounting for 79.3% of all devices used. CONCLUSION: There are effective infection surveillance and control programs in VA NHCUs with a point prevalence of NHAIs of 5.2%.

Quality indicators in the Department of Veterans Affairs nursing home care units: a preliminary assessment.

The authors analyzed the minimum data set quality indicators data aggregated nationally from 134 Department of Veterans Affairs nursing home care units with more than 15,000 long-stay residents (>90 days) yearly for federal fiscal years 2003, 2004, and 2005. Despite an increase in the severity of illness and complexity of services as determined by the minimum data set case-mix indices, most of the minimum data set quality indicators showed an improvement (rate decrease) from fiscal year 2003 to fiscal year 2005, whether examined on a year-to-year basis or by an overall 3-year trend. Nationally, there was a 5.1% increase in average case-mix index, while 14 of 24 quality indicators showed a decrease in the prevalence/ incidence rates and only 4 quality indicators showed increased rates. These minimum data set results provide important information for Veterans Affairs quality managers regarding areas of achievement and also identify areas to be targeted for future quality improvement.