Ghrelin signaling contributes to fasting-induced attenuation of hindbrain neural activation and hypophagic responses to systemic cholecystokinin in rats.

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.

Interoceptive modulation of neuroendocrine, emotional, and hypophagic responses to stress.

Periods of caloric deficit substantially attenuate many centrally mediated responses to acute stress, including neural drive to the hypothalamic-pituitary-adrenal (HPA) axis, anxiety-like behavior, and stress-induced suppression of food intake (i.e., stress hypophagia). It is posited that this stress response plasticity supports food foraging and promotes intake during periods of negative energy balance, even in the face of other internal or external threats, thereby increasing the likelihood that energy stores are repleted. The mechanisms by which caloric deficit alters central stress responses, however, remain unclear. The caudal brainstem contains two distinct populations of stress-recruited neurons [i.e., noradrenergic neurons of the A2 cell group that co-express prolactin-releasing peptide (PrRP+ A2 neurons), and glucagon-like peptide 1 (GLP-1) neurons] that also are responsive to interoceptive feedback about feeding and metabolic status. A2/PrRP and GLP-1 neurons have been implicated anatomically and functionally in the central control of the HPA axis, anxiety-like behavior, and stress hypophagia. The current review summarizes a growing body of evidence that caloric deficits attenuate physiological and behavioral responses to acute stress as a consequence of reduced recruitment of PrRP+ A2 and hindbrain GLP-1 neurons, accompanied by reduced signaling to their brainstem, hypothalamic, and limbic forebrain targets.

Two Novel Psychomotor Tasks in Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (INPH) is a neurological disorder presenting with gait, cognitive, and bladder symptoms in the context of ventricular enlargement. Although gait is the primary indicator for treatment candidacy and outcome, additional monitoring tools are needed. Line Tracing Test (LTT) and Serial Dotting Test (SDT), two psychomotor tasks, have been introduced as potential outcome measures but have not been widely studied. This preliminary study examined whether LTT and SDT are sensitive to motor dysfunction in INPH and determined if accuracy and time are important aspects of performance. METHODS: Eighty-four INPH subjects and 36 healthy older adults were administered LTT and SDT. Novel error scoring procedures were developed to make scoring practical and efficient; interclass correlation showed good reliability of scoring procedures for both tasks (0.997; p<.001). RESULTS: The INPH group demonstrated slower performance on SDT (p<.001) and made a greater number of errors on both tasks (p<.001). Combined Time/Error scores revealed poorer performance in the INPH group for original-LTT (p<.001), modified-LTT (p ≤ .001) and SDT (p<.001). CONCLUSIONS: These findings indicate LTT and SDT may prove useful for monitoring psychomotor skills in INPH. While completion time reflects impaired processing speed, reduced accuracy may suggest planning and self-monitoring difficulties, aspects of executive functioning known to be compromised in INPH. This is the first study to underscore the importance of performance accuracy in INPH and introduce practical/reliable error scoring for these tasks. Future work will establish reliability and validity of these measures and determine their utility as outcome tools.

Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by "Silencing" Central Glucagon-Like Peptide 1 Signaling in Rats.

Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast "silences" GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress. SIGNIFICANCE STATEMENT: The results from this study reveal a potential central mechanism for the "metabolic tuning" of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats, reduces or blocks the ability of acute stress to activate hindbrain neurons that are immunoreactive for either prolactin-releasing peptide or glucagon-like peptide 1, and attenuates the activation of their stress-sensitive projection targets in the limbic forebrain. In nonfasted rats, central antagonism of glucagon-like peptide 1 receptors partially mimics the effect of an overnight fast by blocking the ability of acute stress to inhibit food intake, and by attenuating stress-induced activation of hindbrain and limbic forebrain neurons. We propose that caloric restriction attenuates behavioral and physiological responses to acute stress by "silencing" central glucagon-like peptide 1 signaling pathways.

The potential of accelerating early detection of autism through content analysis of YouTube videos.

Autism is on the rise, with 1 in 88 children receiving a diagnosis in the United States, yet the process for diagnosis remains cumbersome and time consuming. Research has shown that home videos of children can help increase the accuracy of diagnosis. However the use of videos in the diagnostic process is uncommon. In the present study, we assessed the feasibility of applying a gold-standard diagnostic instrument to brief and unstructured home videos and tested whether video analysis can enable more rapid detection of the core features of autism outside of clinical environments. We collected 100 public videos from YouTube of children ages 1-15 with either a self-reported diagnosis of an ASD (N = 45) or not (N = 55). Four non-clinical raters independently scored all videos using one of the most widely adopted tools for behavioral diagnosis of autism, the Autism Diagnostic Observation Schedule-Generic (ADOS). The classification accuracy was 96.8%, with 94.1% sensitivity and 100% specificity, the inter-rater correlation for the behavioral domains on the ADOS was 0.88, and the diagnoses matched a trained clinician in all but 3 of 22 randomly selected video cases. Despite the diversity of videos and non-clinical raters, our results indicate that it is possible to achieve high classification accuracy, sensitivity, and specificity as well as clinically acceptable inter-rater reliability with nonclinical personnel. Our results also demonstrate the potential for video-based detection of autism in short, unstructured home videos and further suggests that at least a percentage of the effort associated with detection and monitoring of autism may be mobilized and moved outside of traditional clinical environments.

Systemic leptin dose-dependently increases STAT3 phosphorylation within hypothalamic and hindbrain nuclei.

Leptin released peripherally acts within the central nervous system (CNS) to modulate numerous physiological and behavioral functions. Histochemical identification of leptin-responsive CNS cells can reveal the specific cellular phenotypes and neural circuits through which leptin signaling modulates these functions. Leptin signaling elicits phosphorylation of signal transducer and activator of transcription 3 (pSTAT3), making pSTAT3-immunoreactivity (ir) a useful proxy for identifying leptin-responsive cells. Relatively low systemic doses of leptin (i.e., 10-130 µg/kg body wt) are sufficient to decrease food intake, inhibit gastric emptying, and increase sympathetic activity, but there are no histological reports of central pSTAT3-ir following leptin doses within this range. Considering this, we quantified central pSTAT3-ir in rats after intraperitoneal injections of leptin at doses ranging from 50 to 800 µg/kg body wt. Tissue sections were processed to identify pSTAT3-ir alone or in combination with immunolabeling for cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1), prolactin-releasing peptide (PrRP), or dopamine-ß-hydroxylase (DßH). Leptin doses as low as 50, 100, and 200 µg/kg body wt significantly increased the number of pSTAT3-ir cells in the arcuate nucleus of the hypothalamus (ARC), nucleus of the solitary tract (NTS), and ventromedial nucleus of the hypothalamus, respectively, and also led to robust pSTAT3 labeling in neural processes. The differential dose-dependent increases in pSTAT3-ir across brain regions provide new information regarding central leptin sensitivity. Within the ARC, CART-ir and pSTAT3-ir were often colocalized, consistent with evidence of leptin sensitivity in this neural population. Conversely, within the NTS, pSTAT3 only rarely colocalized with PrRP and/or DßH, and never with GLP-1.

Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study.

AIM: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. METHODS: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [(18)F]fluorodeoxyglucose positron emission computed tomography (FDG-PET) and magnetic resonance imaging, and a complete neuropsychological battery. RESULTS: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex. CONCLUSIONS: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes.

Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats.

Systemic administration of sulfated cholecystokinin-8 (CCK) activates neurons within the hindbrain nucleus of the solitary tract (NTS) that project directly to the paraventricular nucleus of the hypothalamus (PVN), and these projections underlie the ability of exogenous CCK to activate the hypothalamic-pituitary-adrenal (HPA) stress axis. CCK inhibits food intake, increases NTS neuronal cFos expression, and activates the HPA axis in a dose-dependent manner. While the hypophagic effects of exogenous CCK are attenuated in food-deprived rats, CCK dose-response relationships for NTS and hypothalamic activation in fed and fasted rats are unknown. Within the NTS, noradrenergic A2 and glucagon-like peptide-1 (GLP-1) neurons express cFos after high doses of CCK, and both neuronal populations project directly to the medial parvocellular (mp)PVN. We hypothesized that increasing and correlated proportions of A2, GLP-1, and mpPVN neurons would express cFos in rats after increasing doses of CCK, and that food deprivation would attenuate both hindbrain and hypothalamic neural activation. To test these hypotheses, ad libitum-fed (ad lib) and overnight food-deprived (DEP) rats were anesthetized and perfused with fixative 90min after i.p. injection of 1.0ml saline vehicle containing CCK at doses of 0, 3, or 10µg/kg BW. Additional ad lib and DEP rats served as non-handled (NH) controls. Brain tissue sections were processed for dual immunocytochemical localization of cFos and dopamine-ß-hydroxylase to identify A2 neurons, or cFos and GLP-1. Compared to negligible A2 cFos activation in NH control rats, i.p. vehicle and CCK dose-dependently increased A2 activation, and this was significantly attenuated by DEP. DEP also attenuated mpPVN cFos expression across all treatment groups, and A2 activation was strongly correlated with mpPVN activation in both ad lib and DEP rats. In ad lib rats, large and similar numbers of GLP-1 neurons expressed cFos across all i.p. treatment groups, regardless of CCK dose. Surprisingly, DEP nearly abolished baseline GLP-1 cFos expression in NH controls, and also in rats after i.p. injection of vehicle or CCK. We conclude that CCK-induced hypothalamic cFos activation is strongly associated with A2 activation, whereas the relationship between mpPVN and GLP-1 activation is less clear. Furthermore, activation of A2, GLP-1, and mpPVN neurons is significantly modulated by feeding status, suggesting a mechanism through which food intake and metabolic state might impact hypothalamic neuroendocrine responses to homeostatic challenge.

Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing Peptide or glucagon-like Peptide 1.

Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to-day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA) neurons within the caudal nucleus of the solitary tract (cNST; A2 cell group) that is immunopositive for prolactin-releasing peptide (PrRP). The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1). Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake.