Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus.

The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer's disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development.

Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia.

The counterregulatory response to hypoglycemia (CRR), which ensures a sufficient glucose supply to the brain, is an essential survival function. It is orchestrated by incompletely characterized glucose-sensing neurons, which trigger a coordinated autonomous and hormonal response that restores normoglycemia. Here, we investigate the role of hypothalamic Tmem117, identified in a genetic screen as a regulator of CRR.

Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion.

The counterregulatory response to hypoglycemia that restores normal blood glucose levels is an essential physiological function. It is initiated, in large part, by incompletely characterized brain hypoglycemia sensing neurons that trigger the secretion of counterregulatory hormones, in particular glucagon, to stimulate hepatic glucose production. In a genetic screen of recombinant inbred BXD mice we previously identified Agpat5 as a candidate regulator of hypoglycemia-induced glucagon secretion.

Glucokinase neurons of the paraventricular nucleus of the thalamus sense glucose and decrease food consumption.

The paraventricular nucleus of the thalamus (PVT) controls goal-oriented behavior through its connections to the nucleus accumbens (NAc). We previously characterized Glut2 neurons that are activated by hypoglycemia, and which increase sucrose seeking behavior through their glutamatergic projections to the NAc. Here, we identified glucokinase ()-expressing neurons of the PVT (Gck) and generated a mouse line expressing the Cre recombinase from the glucokinase locus ( mice).

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis.

The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized.

EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis.

Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown.

Hypoglycemia-Sensing Neurons of the Ventromedial Hypothalamus Require AMPK-Induced Txn2 Expression but Are Dispensable for Physiological Counterregulation.

The ventromedial nucleus of the hypothalamus (VMN) is involved in the counterregulatory response to hypoglycemia. VMN neurons activated by hypoglycemia (glucose-inhibited [GI] neurons) have been assumed to play a critical although untested role in this response. Here, we show that expression of a dominant negative form of AMPK or inactivation of AMPK and subunit genes in Sf1 neurons of the VMN selectively suppressed GI neuron activity.

Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow.

Glucose transporter 2 ()-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if -positive cells can influence another response to hypoglycemia, i.e.

GLUT2-Expressing Neurons as Glucose Sensors in the Brain: Electrophysiological Analysis.

Brain glucose sensing plays an essential role in the regulation of energy homeostasis. Recent publications report that neurons expressing glucose transporter GLUT2 act as glucose sensors in different regions of the brain and contribute to the control of glucose homeostasis and feeding behavior. In this chapter we describe the methods used to explore glucose sensing in genetically tagged GLUT2-expressing neurons with slice electrophysiology.

Homeostasis Meets Motivation in the Battle to Control Food Intake.

Signals of energy homeostasis interact closely with neural circuits of motivation to control food intake. An emerging hypothesis is that the transition to maladaptive feeding behavior seen in eating disorders or obesity may arise from dysregulation of these interactions. Focusing on key brain regions involved in the control of food intake (ventral tegmental area, striatum, hypothalamus, and thalamus), we describe how activity of specific cell types embedded within these regions can influence distinct components of motivated feeding behavior.

Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase.

Glucokinase (Gck) is a critical regulator of glucose-induced insulin secretion by pancreatic β-cells. It has been suggested to also play an important role in glucose signaling in neurons of the ventromedial hypothalamic nucleus (VMN), a brain nucleus involved in the control of glucose homeostasis and feeding. To test the role of Gck in VMN glucose sensing and physiological regulation, we studied mice with genetic inactivation of the Gck gene in Sf1 neurons of the VMN (Sf1Gck(-/-) mice).

Glucose-responsive neurons of the paraventricular thalamus control sucrose-seeking behavior.

Feeding behavior is governed by homeostatic needs and motivational drive to obtain palatable foods. Here, we identify a population of glutamatergic neurons in the paraventricular thalamus of mice that express the glucose transporter Glut2 (encoded by Slc2a2) and project to the nucleus accumbens. These neurons are activated by hypoglycemia and, in freely moving mice, their activation by optogenetics or Slc2a2 inactivation increases motivated sucrose-seeking but not saccharin-seeking behavior.

Brain glucose sensing in homeostatic and hedonic regulation.

Glucose homeostasis as well as homeostatic and hedonic control of feeding is regulated by hormonal, neuronal, and nutrient-related cues. Glucose, besides its role as a source of metabolic energy, is an important signal controlling hormone secretion and neuronal activity, hence contributing to whole-body metabolic integration in coordination with feeding control. Brain glucose sensing plays a key, but insufficiently explored, role in these metabolic and behavioral controls, which when deregulated may contribute to the development of obesity and diabetes.

Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion.

Glucose-sensing neurons in the brainstem participate in the regulation of energy homeostasis but have been poorly characterized because of the lack of specific markers to identify them. Here we show that GLUT2-expressing neurons of the nucleus of the tractus solitarius form a distinct population of hypoglycemia-activated neurons. Their response to low glucose is mediated by reduced intracellular glucose metabolism, increased AMP-activated protein kinase activity, and closure of leak K(+) channels.

Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids.

The prevalence of obesity has markedly increased over the past few decades. Exploration of how hunger and satiety signals influence the reward system can help us understand non-homeostatic feeding. Insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding.

GABA neurons of the VTA drive conditioned place aversion.

Salient but aversive stimuli inhibit the majority of dopamine (DA) neurons in the ventral tegmental area (VTA) and cause conditioned place aversion (CPA). The cellular mechanism underlying DA neuron inhibition has not been investigated and the causal link to behavior remains elusive. Here, we show that GABA neurons of the VTA inhibit DA neurons through neurotransmission at GABA(A) receptors.

Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.

Background: Addictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.

Neural bases for addictive properties of benzodiazepines.

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive.

RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area.

Agonists of GABA(B) receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABA(B) receptor agonists such as gamma-hydroxybutyrate (GHB) and its derivatives.