Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. ...Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.
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•Genetic deconstruction of vagal afferent types that monitor and control digestion•GPR65 neurons target intestinal villi, detect nutrients, and control gut motility•GLP1R neurons form specialized terminals that detect stomach and intestine stretch•Coding of autonomic inputs in vagal ganglion and brainstem
Two types of neurons sending signals from the gut to the brain control digestion. One densely innervates intestinal villi and detects food, while another targets stomach and intestinal muscle and senses stretch.
Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive ...neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT
+) or excitatory (glutamatergic, VGLUT2
+). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.
► Uncertainty exists regarding the neurons mediating leptin's antiobesity effects ► Leptin receptors on GABAergic, but not glutamatergic, neurons play a large role ► Leptin, via presynaptic GABAergic neurons, disinhibits postsynaptic POMC neurons ► A GABA-POMC circuit probably drives, at least in part, leptin's antiobesity effects
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. ...To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
► NMDARs on AgRP but not POMC neurons regulate feeding and body weight ► AgRP neurons have many dendritic spines; POMC neurons, in contrast, are aspiny ► Fasting activation of AgRP neurons requires NMDARs and increased excitatory tone ► Increased excitatory tone is likely caused by NMDAR-driven dendritic spinogenesis
AgRP neurons drive feeding behavior. Liu et al. find that fasting activation of AgRP neurons requires postsynaptic NMDARs, promoting dendritic spinogenesis, likely synaptogenesis, and increasing excitatory tone. Thus, NMDAR-mediated synaptic plasticity is a key regulator of AgRP neurons and feeding behavior.
New neuroscientific techniques have enabled investigators to assess the neurons and pathways involved in essential drives for food, water, and salt and to define the elements that might be targeted ...to address abnormalities in homeostasis leading to disease.
The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system ...leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
•Optogenetic excitation of nucleus accumbens dynorphin cells elicits dynorphin release•Discrete accumbens shell dynorphinergic populations drive either aversion or reward•These two nucleus accumbens subregions can be bi-directionally controlled•Both aversive and rewarding behaviors require kappa opioid receptors
Al-Hasani et al. show that dynorphin is necessary to drive opposing motivational states within subregions of the nucleus accumbens shell. Dynorphinergic neurons in the ventral shell drive aversion whereas in the dorsal shell they drive preference and reward seeking.
The hypothalamus Saper, Clifford B.; Lowell, Bradford B.
Current biology,
12/2014, Letnik:
24, Številka:
23
Journal Article
Recenzirano
Odprti dostop
The hypothalamus is one of the oldest and smallest parts of the brain, constituting just 4 gm of the 1400 gm of adult human brain weight. And yet this tiny area contains highly conserved neural ...circuitry that controls basic life functions: these include energy metabolism, from feeding through digestion, metabolic control, and energy expenditure; fluid and electrolyte balance, from drinking through fluid absorption and excretion; thermoregulation, from choice of environment through heat production and conservation, and fever responses; wake-sleep cycles and emergency responses to stressors in the environment; and reproduction, from reproductive hormone control through mating, pregnancy, birth, and suckling. In this Primer, we will give an overview of the structure of the hypothalamus, and outline what we know about how that relates to its functional circuitry.
The hypothalamus is a tiny, ancient part of the brain, which contains highly conserved circuitry that controls a number of essential, basic life functions. In this Primer, Saper and Lowell give an overview of the structure of the hypothalamus, and how that relates to its functional circuitry.
Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated ...through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons, form a microcircuit that transmits and gates mechanical pain.
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•Intersectional ablation of dorsal spinal excitatory and inhibitory neurons•SOM+ excitatory neurons are required to sense acute and chronic mechanical pain•Dyn+ neurons prevent Aβ fibers from activating SOM+ pain transmission neurons•Identification of spinal circuits that transmit and gate mechanical pain
Genetic manipulations in the spinal cord reveal the identity of neurons transmitting and gating pain. Spinal somastatin-positive excitatory neurons receive input from peripheral nociceptors and Aβ mechanoreceptors, which are in turns gated by dynorphin-expressing inhibitory neurons.
AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. ...Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity.
•Fasting stimulates AMPK activity in hypothalamic AgRP neurons•AMPK in AgRP neurons is necessary and sufficient for fasting synaptic plasticity•AMPK phosphorylates PAK and activates PAK signaling pathway both in vitro and in vivo•AMPK-PAK signaling in AgRP neurons is required for fasting-induced synaptic plasticity
Kong et al. employed neuron-specific approaches and established that fasting-stimulated AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced AgRP neuron excitatory synaptic plasticity, neuronal activation, and feeding, and requires p21-activated kinase (PAK) signaling.
Prior mouse genetic research has set the stage for a deep understanding of appetite regulation. This goal is now being realized through the use of recent technological advances, such as the ability ...to map connectivity between neurons, manipulate neural activity in real time, and measure neural activity during behavior. Indeed, major progress has been made with regard to meal-related gut control of appetite, arcuate nucleus-based hypothalamic circuits linking energy state to the motivational drive, hunger, and, finally, limbic and cognitive processes that bring about hunger-mediated increases in reward value and perception of food. Unexpected findings are also being made; for example, the rapid regulation of homeostatic neurons by cues that predict future food consumption. The aim of this review is to cover the major underpinnings of appetite regulation, describe recent advances resulting from new technologies, and synthesize these findings into an updated view of appetite regulation.
Andermann and Lowell review the major underpinnings of appetite control; integrate recent advances resulting from anatomical tracing, physiology, and manipulation studies of specific populations of neurons recruited by various feeding behaviors; and put forward a conceptual framework for future investigations.
Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism.
O Boss ,
T Hagen and
B B Lowell
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical ...School, Boston, Massachusetts, USA.
Abstract
Mitochondria use energy derived from fuel combustion to create a proton electrochemical gradient across the mitochondrial
inner membrane. This intermediate form of energy is then used by ATP synthase to synthesize ATP. Uncoupling protein-1 (UCP1)
is a brown fat-specific mitochondrial inner membrane protein with proton transport activity. UCP1 catalyzes a highly regulated
proton leak, converting energy stored within the mitochondrial proton electrochemical potential gradient to heat. This uncouples
fuel oxidation from conversion of ADP to ATP. In rodents, UCP1 activity and brown fat contribute importantly to whole-body
energy expenditure. Recently, two additional mitochondrial carriers with high similarity to UCP1 were molecularly cloned.
In contrast to UCP1, UCP2 is expressed widely, and UCP3 is expressed preferentially in skeletal muscle. Biochemical studies
indicate that UCP2 and UCP3, like UCP1, have uncoupling activity. While UCP1 is known to play an important role in regulating
heat production during cold exposure, the biological functions of UCP2 and UCP3 are unknown. Possible functions include 1)
control of adaptive thermogenesis in response to cold exposure and diet, 2) control of reactive oxygen species production
by mitochondria, 3) regulation of ATP synthesis, and 4) regulation of fatty acid oxidation. This article will survey present
knowledge regarding UCP1, UCP2, and UCP3, and review proposed functions for the two new uncoupling proteins.
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