Free-choice high-fat diet consumption reduces lateral hypothalamic GABAergic activity, without disturbing neural response to sucrose drinking in mice.

Nutrition can influence the brain and affect its regulation of food intake, especially that of high-palatable foods. We hypothesize that fat and sugar have interacting effects on the brain, and the lateral hypothalamus (LH) is a prime candidate to be involved in this interaction. The LH is a heterogeneous area, crucial for regulating consummatory behaviors, and integrating homeostatic and hedonic needs. GABAergic LH neurons stimulate feeding when activated, and are responsive to consummatory behavior while encoding sucrose palatability. Previously, we have shown that glutamatergic LH neurons reduce their activity in response to sugar drinking and that this response is disturbed by a free-choice high-fat diet (fcHFD). Whether GABAergic LH neurons, and their response to sugar, is affected by a fcHFD is yet unknown. Using head-fixed two-photon microscopy, we analyzed activity changes in LHVgat neuronal activity in chow or fcHFD-fed mice in response to water or sucrose drinking. A fcHFD decreased overall LHVgat neuronal activity, without disrupting the sucrose-induced increase. When focusing on the response per unique neuron, a vast majority of neurons respond inconsistently over time. Thus, a fcHFD dampens overall LH GABAergic activity, while it does not disturb the response to sucrose. The inconsistent responding over time suggests that it is not one specific subpopulation of LH GABAergic neurons that is driving these behaviors, but rather a result of the integrative properties of a complex neural network. Further research should focus on determining how this dampening of LH GABAergic activity contributes to hyperphagia and the development of obesity.

Disruption of lateral hypothalamic calorie detection by a free choice high fat diet.

During the last few decades, the consumption of low-calorie sweeteners, as a substitute for caloric sweeteners, has sharply increased. Although research shows that caloric versus low-calorie sweeteners can have differential effects on the brain, it is unknown which neuronal populations are responsible for detecting the difference between the two types of sweeteners. Using in vivo two-photon calcium imaging, we investigated how drinking sucrose or sucralose (a low-calorie sweetener) affects the activity of glutamatergic neurons in the lateral hypothalamus. Furthermore, we explored the consequences of consuming a free-choice high fat diet on the calorie detection abilities of these glutamatergic neurons. We found that glutamatergic neurons indeed can discriminate sucrose from water and sucralose, and that consumption of a free-choice high fat diet shifts the glutamatergic neuronal response from sucrose-specific to sucralose-specific, thereby disrupting calorie detection. These results highlight the disruptive effects of a diet high in saturated fat on calorie detection in the lateral hypothalamus.

Quantitative analysis of in-vivo microbubble distribution in the human brain.

Microbubbles (MB) are widely used as contrast agents to perform contrast-enhanced ultrasound (CEUS) imaging and as acoustic amplifiers of mechanical bioeffects incited by therapeutic-level ultrasound. The distribution of MBs in the brain is not yet fully understood, thereby limiting intra-operative CEUS guidance or MB-based FUS treatments. In this paper we describe a robust platform for quantification of MB distribution in the human brain, allowing to quantitatively discriminate between tumoral and normal brain tissues and we provide new information regarding real-time cerebral MBs distribution. Intraoperative CEUS imaging was performed during surgical tumor resection using an ultrasound machine (MyLab Twice, Esaote, Italy) equipped with a multifrequency (3-11 MHz) linear array probe (LA332) and a specific low mechanical index (MI < 0.4) CEUS algorithm (CnTi, Esaote, Italy; section thickness, 0.245 cm) for non-destructive continuous MBs imaging. CEUS acquisition is started by enabling the CnTI PEN-M algorithm automatically setting the MI at 0.4 with a center frequency of 2.94 MHz-10 Hz frame rate at 80 mm-allowing for continuous non-destructive MBs imaging. 19 ultrasound image sets of adequate length were selected and retrospectively analyzed using a custom image processing software for quantitative analysis of echo power. Regions of interest (ROIs) were drawn on key structures (artery-tumor-white matter) by a blinded neurosurgeon, following which peak enhancement and time intensity curves (TICs) were quantified. CEUS images revealed clear qualitative differences in MB distribution: arteries showed the earliest and highest enhancement among all structures, followed by tumor and white matter regions, respectively. The custom software built for quantitative analysis effectively captured these differences. Quantified peak intensities showed regions containing artery, tumor or white matter structures having an average MB intensity of 0.584, 0.436 and 0.175 units, respectively. Moreover, the normalized area under TICs revealed the time of flight for MB to be significantly lower in brain tissue as compared with tumor tissue. Significant heterogeneities in TICs were also observed within different regions of the same brain lesion. In this study, we provide the most comprehensive strategy for accurate quantitative analysis of MBs distribution in the human brain by means of CEUS intraoperative imaging. Furthermore our results demonstrate that CEUS imaging quantitative analysis enables discernment between different types of brain tumors as well as regions and structures within the brain. Similar considerations will be important for the planning and implementation of MB-based imaging or treatments in the future.