The associations between consumption of a high-fat or ‘Western’ diet and metabolic disorders such as obesity, diabetes, and cardiovascular disease have long been recognized and a great deal of evidence now suggests that diets high in fat can also have a profound impact on the brain, behavior, and cognition. Here, we will review the techniques most often used to assess learning and memory in rodent models and discuss findings from studies assessing the cognitive effects of high-fat diet consumption. The review will then consider potential underlying mechanisms in the brain and conclude by reviewing emerging literature suggesting that maternal consumption of a high-fat diet may have effects on the learning and memory of offspring.

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The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

OBJECTIVES To examine quality of life (QOL) in nursing home (NH) residents with advanced dementia and identify correlates of QOL near the end of life. DESIGN Cross-sectional data derived from NH records, interviews with residents’ surrogate decision-makers, QOL ratings by NH caregivers, and assessment of residents’ cognitive function. SETTING Three NHs in Maryland. PARTICIPANTS A cohort of NH residents with dementia (n=119), who were either receiving hospice or palliative care or met hospice criteria for dementia, and their surrogates. MEASUREMENTS QOL based on the proxy-rated Alzheimer Disease Related Quality of Life (ADRQL) scale administered to NH staff and validated against a single-item surrogate-rated measure of QOL, the Severe Impairment Rating Scale to measure cognitive function, and dichotomous indicators of neuropsychiatric symptoms (i.e., behavior problems, mood disorders, psychosis/delusions). RESULTS Total ADRQL scores, ranging from 12.4 to 95.1 out of 100, were normally distributed and positively correlated (p<.001) with surrogate-rated QOL. Multiple regression analysis of ADRQL scores showed that residents with higher cognitive function (p<.001, CI = .966 – 1.650) and those receiving pain medication (p=.006, CI = 3.303 – 19.588) had higher QOL, while residents with behavior problems (p=.014, CI = −11.604 – −1.298) had lower QOL. CONCLUSION The ADRQL is a valid indicator of QOL in NH residents with advanced dementia. QOL in this population may be improved near the end of life by appropriate assessment and treatment of pain and more effective management of behavior problems.

Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indicating a need to investigate effects of various risk factors, including diet, across the lifespan. Here, we use a rat model to assess the effects of maternal diet during pregnancy and lactation on cognition and hippocampal gene expression of offspring. Behaviorally, adult male offspring of high-fat fed dams had impaired object recognition memory and impaired spatial memory compared to offspring of chow-fed dams. In hippocampus, we found decreased expression of Insr, Lepr, and Slc2a1 (GLUT1) among offspring of high-fat fed dams at postnatal day 21. The decreased expression of Insr and Lepr persisted at postnatal day 150. Together, these data provide additional evidence to suggest that maternal exposure to high-fat diet during pregnancy and lactation can have lasting effects on the brain, behavior, and cognition on adult offspring.

Genome-wide association studies have implicated the ANK3 locus in bipolar disorder, a major human psychotic illness. ANK3 encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS).We generated a mouse model with conditional disruption of ANK3 in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage-gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to "depressionlike" behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics.B ipolar disorder and schizophrenia are major psychiatric disorders. Bipolar patients experience both mania, with elevated mood and activity, and depression (often triggered by stress), with low mood and activity. Bipolar disorder is often uniquely responsive to lithium (Li). Many loci have been identified by genome-wide association studies (GWASs) for schizophrenia (1). By contrast, fewer loci with genome-wide significance have been identified for bipolar disorder (2), with some overlap, suggesting some shared mechanisms.In a recent large GWAS of bipolar disorder (3), the most significant signal was detected at the ANK3 locus. This finding has been replicated in many (if not all) GWASs of bipolar disorder (3-5). The ANK3 locus is also found to be associated, to a lesser extent, with schizophrenia (6, 7).The ANK3 gene encodes ankyrin-G, a large scaffold protein highly expressed in neurons in the brain (8). Three main brainspecific splice variants encode 190, 270, and 480 kDa polypeptides. The 480-kDa peptide is the major isoform responsible for organization of the components of the axon initial segment (AIS), including the clustering of voltage-gated sodium and potassium channels important for generation of the action potential (9, 10). The 190-kDa isoform is present at dendritic spines (11,12). Many of the risk alleles for ANK3 are in the five-prime upstream region, suggestive of changes of expression (13, 14). Ankyrin-G protein expression was reduced in pyramidal AISs in superficial layers of schizophrenia cortex (15). These data suggest that ANK3 risk alleles can cause ankyrin-G loss of function.In cortex, the AISs of pyramidal n...

Objective: This study aimed to determine how the rat placenta and fetus respond to maternal high-fat (HF) diet during gestation and to identify the possible mechanisms. Methods: Pregnant Sprague-Dawley rats were fed with standard chow (13.5% fat) or HF (60% fat) diet during gestation. Placentas were collected on gestation day 21. Results: HF dams had greater fat mass, higher plasma leptin, lower plasma adiponectin, and impaired glucose tolerance during pregnancy. The placental labyrinth thickness was reduced in both male and female fetuses of HF dams. In HF male placentas, glucose transporter 3 gene expression, system A amino acid transporter (SNAT) 2 gene expression, and SNAT2 protein expression were increased through the activation of the mTORC1 4EBP1 branch. In HF female placentas, gene expression of insulin-like growth factor 2 (IGF2) and IGF2 receptor was elevated compared to placentas of females fed standard chow. Although male and female placentas responded differently to prenatal HF diet exposure, both male and female fetal weight was not altered by maternal HF diet. Conclusions: Placenta responds and adapts to maternal metabolic changes by altering placental layer thickness, mTORC1 signaling, expression of nutrient transporters, and growth factors in a sex-specific manner.Obesity (2017) 25, 909-919.

The maternal environment during pregnancy is critical for fetal development and perinatal perturbations can prime offspring disease risk. Here, we briefly review evidence linking two wellcharacterized maternal stressors -psychosocial stress and infection -to increased neuropsychiatric risk in offspring. In the current climate of increasing obesity and globalization of the Western-style diet, maternal overnutrition emerges as a pressing public health concern. We focus our attention on recent epidemiological and animal model evidence showing that, like psychosocial stress and infection, maternal overnutrition can also increase offspring neuropsychiatric risk. Using lessons learned from the psychosocial stress and infection literature, we discuss how altered maternal and placental physiology in the setting of overnutrition may contribute to abnormal fetal development and resulting neuropsychiatric outcomes. A better understanding of converging pathophysiological pathways shared between stressors may enable development of interventions against neuropsychiatric illnesses that may be beneficial across stressors.