Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from αCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in αCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior.

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There is mounting literature that examines brain activation during tasks of working memory in individuals with neurological disorders such as traumatic brain injury. These studies represent a foundation for understanding the functional brain changes that occur after moderate and severe traumatic brain injury, but the focus on topographical brain-'activation' differences ignores potential alterations in how nodes communicate within a distributed neural network. The present study makes use of the most recently developed connectivity modelling (extended-unified structural equation model) to examine performance during a well-established working-memory task (the n-back) in individuals sustaining moderate and severe traumatic brain injury. The goal is to use the findings observed in topographical activation analysis as the basis for second-level effective connectivity modelling. Findings reveal important between-group differences in within-hemisphere connectivity during task acquisition, with the control sample demonstrating rapid within-left hemisphere connectivity increases and the traumatic brain injury sample demonstrating consistently elevated within-right hemisphere connectivity. These findings also point to important maturational effects from 'early' to 'late' during task performance, including diminished right prefrontal cortex involvement and an anterior to posterior shift in connectivity with increased task exposure. We anticipate that this approach to functional imaging data analysis represents an important future direction for understanding how neural plasticity is expressed in brain disorders.

Purpose In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycemic continuum and may be associated with markers of inflammation. Methods Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percent change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c-reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. Results Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared to healthy controls (peak dilation: prediabetic subjects 3.3 ± 1.8 %, diabetic subjects 3.3 ± 2.1% controls 5.6 ± 2.6%, p = .001; relative amplitude: prediabetic subjects 4.3 ± 2.2%, diabetic subjects 5.0 ± 2.6% and control subjects 7.2 ± 3.2%, p = .003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. Conclusion Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs-CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk.

Previous studies of the BOLD response in the injured brain have revealed neural recruitment relative to controls during working memory tasks in several brain regions, most consistently the right prefrontal cortex and anterior cingulate cortices. We previously proposed that the recruitment observed in this literature represents auxiliary support resources, and that recruitment of PFC is not abnormal or injury specific and should reduce as novelty and challenge decrease. The current study directly tests this hypothesis in the context of practice of a working memory task. It was hypothesized that individuals with brain injury would demonstrate recruitment of previously indicated regions, behavioral improvement following task practice, and a reduction in the BOLD signal in recruited regions after practice. Individuals with traumatic brain injury and healthy controls performed the n-back during fMRI acquisition, practiced each task out of the scanner, and returned to the scanner for additional fMRI n-back acquisition. Statistical parametric maps demonstrated a number of regions of recruitment in the 1-back in individuals with brain injury and a number of corresponding regions of reduced activation in individuals with brain injury following practice in both the 1-back and 2-back. Regions of interest demonstrated reduced activation following practice, including the anterior cingulate and right prefrontal cortices. Individuals with brain injury demonstrated modest behavioral improvements following practice. These findings suggest that neural recruitment in brain injury does not represent reorganization but a natural extension of latent mechanisms that engage transiently and are contingent upon cerebral challenge.

ABSTRACT.Purpose: The retinal blood vessels provide a unique way to directly examine the human microvasculature, which is frequently damaged in individuals with diabetes. Previous studies have demonstrated that retinal flickering light-induced vasodilation and hyperoxia-induced vasoconstriction may operate by enhancing or reducing similar vasoregulatory factor(s), but a comparison between these two provocative stimuli in individuals with diabetes has not been studied. The purpose of the study was to examine the association between retinal flickering light-induced vasodilation and retinal hyperoxia-induced vasoconstriction in type 2 diabetic subjects and in healthy controls. Methods: Twenty men and women with type 2 diabetes and 10 men and women without diabetes between 21 and 75 years of age were recruited. Changes in retinal artery and vein diameters to flickering light and during hyperoxia (100% oxygen) stimuli were measured on the same visit using a noninvasive retinal imaging device (Dynamic Vessel Analyzer, Imedos Inc., Germany). Results: Compared with controls, diabetic subjects had impaired arterial vasodilator and vasoconstrictor responses to both flickering light and hyperoxia, respectively (both p < 0.001). Merging both groups, an inverse correlation (r = )0.56; p = 0.003) between the retinal artery's responses to flickering light-induced vasodilation and hyperoxia-induced vasoconstriction was demonstrated independent of glucose or insulin levels. Conclusion: This suggests that both responses are attenuated to a similar degree in diabetic subjects and that the attenuation to both stimuli can be observed in retinal arteries and veins. This would suggest that similar vasoregulatory factor(s) might in part help to explain the retinal diameter responses between the two stimuli. One suggested common vasoregulator of vascular tone is nitric oxide; however, other factor(s) may be involved, which contribute to this association and require further research.

Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry.

Approximately 1.4 million people in the United States sustain a traumatic brain injury (TBI) each year, resulting in more than 235 000 hospitalizations and 50 000 deaths. An estimated 5.3 million Americans have current long-term disabilities as a result of TBI, which results in an estimated $60 billion in healthcare expenditures. Mild TBI (mTBI), which accounts for 80% to 90% of all cases, is the most prevalent form of brain injury in athletes. Many of these traumas still remain undetected, as they are difficult to diagnose. New biomarkers of TBI may allow more rapid diagnosis of TBI, improving early identification and treatment, and could help to predict clinical outcome. The field of TBI biomarkers is rapidly evolving. This chapter will discuss some of the most clinically relevant biomarkers for TBI that have been recently studied in human subjects.