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Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate–putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. Insulin signals satiety after a meal; however, the rising incidence of obesity and chronic insulin elevation suggests that insulin may also signal reward. Here, Stouffer et al . show that insulin amplifies dopamine release in rodent striatum depending on diet, and that striatal insulin can influence food choice.

Reward-seeking behaviors depend critically on dopamine signaling—dopamine neurons encode reward-related information by switching from tonic to phasic (burst-like) activity. Using guinea pig brain slices, we show that nicotine, like cocaine and amphetamine, acts directly in striatum where it enhances dopamine release during phasic but not tonic activity. This amplification provides a mechanism for nicotine facilitation of reward-related dopamine signals, including responses to other primary reinforcers that govern nicotine dependence in smokers.

Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor–nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states.

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity. Dopaminergic circuits are implicated in exploratory motor behaviour and are modulated by acetylcholine. Using transgenic mouse models, Patel et al . find that loss of forebrain acetylcholine results in exaggerated dopamine efflux and hyperactivity, whereas loss of brainstem acetylcholine leads to hypoactivity.

Aging is often accompanied by a decline in mobility across species, which can be improved by aerobic exercise, even in individuals with Parkinson’s disease. We showed previously that 30 days of voluntary wheel-running exercise in young male mice leads to enhanced release of the motor-system transmitter, dopamine (DA), in ex vivo corticostriatal slices. Here we tested whether voluntary exercise also increases DA release in aging (12 months old) mice of both sexes, and whether this is associated with improved motor performance. Mice were allowed unlimited access to a rotating (runners) or a locked (controls) wheel for 30 days. Motor behavior was then assessed, and electrically evoked DA release was quantified in slices from these animals using fast-scan cyclic voltammetry. Although daily running distance for females was nearly twice that of males, runners of both sexes showed comparable increases in evoked DA release in dorsolateral striatum and in nucleus accumbens core and shell compared to age- and sex-matched controls. Runners of both sexes showed an increase in locomotion velocity and improved motor coordination. Thus, voluntary exercise boosts striatal DA release and improves motor performance in aging mice, providing new insights into the benefits of exercise in aging humans.

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins.

The neurotransmitter dopamine facilitates learning, motivation and movement. Evidence of its release independently of the activity of dopamine-producing neurons in rat brains forces a rethink of dopamine regulation. Dopamine release can occur independently of neuronal activation.

In many cells, ATP-sensitive K + channels (K ATP channels) couple metabolic state to excitability. In pancreatic beta cells, for example, this coupling regulates insulin release. Although K ATP channels are abundantly expressed in the brain, their physiological role and the factors that regulate them are poorly understood. One potential regulator is H 2 O 2 . We reported previously that dopamine (DA) release in the striatum is modulated by endogenous H 2 O 2 , generated downstream from glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor activation. Here we investigated whether H 2 O 2 -sensitive K ATP channels contribute to DA-release modulation by glutamate and γ-aminobutyric acid (GABA). This question is important because DA–glutamate interactions underlie brain functions, including motor control and cognition. Synaptic DA release was evoked by using local electrical stimulation in slices of guinea pig striatum and monitored in real time with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. The K ATP -channel antagonist glibenclamide abolished the H 2 O 2 -dependent increase in DA release usually seen with AMPA-receptor blockade by GYKI-52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H -2,3-benzodiazepine hydrochloride] and the decrease in DA release seen with GABA-type-A-receptor blockade by picrotoxin. In contrast, 5-hydroxydecanoate, a mitochondrial K ATP -channel blocker, was ineffective, as were sulpiride, a D 2 -receptor antagonist, and tertiapin, a G protein-coupled K + -channel inhibitor. Diazoxide, a sulfonylurea receptor 1 (SUR1)selective K ATP -channel opener, prevented DA modulation by H 2 O 2 , glutamate, and GABA, whereas cromakalim, a SUR2-selective opener, did not. Thus, endogenous H 2 O 2 activates SUR1-containing K ATP channels in the plasma membrane to inhibit DA release. These data not only demonstrate that K ATP channels can modulate CNS transmitter release in response to fast-synaptic transmission but also introduce H 2 O 2 as a K ATP -channel regulator.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.

Many retinal ganglion cells are coupled via gap junctions with neighboring amacrine cells and ganglion cells. We investigated the extent and dynamics of coupling in one such network, the OFF α ganglion cell of rabbit retina and its associated amacrine cells. We also observed the relative spread of Neurobiotin injected into a ganglion cell in the presence of modulators of gap junctional permeability. We found that gap junctions between amacrine cells were closed via stimulation of a D1 dopamine receptor, while the gap junctions between ganglion cells were closed via stimulation of a D2 dopamine receptor. The pairs of hemichannels making up the heterologous gap junctions between the ganglion and amacrine cells were modulated independently, so that elevations of cAMP in the ganglion cell open the ganglion cell hemichannels, while elevations of cAMP in the amacrine cell close its hemichannels. We also measured endogenous dopamine release from an eyecup preparation and found a basal release from the dark-adapted retina of approximately 2 pmol/min during the day. Maximal stimulation with light increased the rate of dopamine release from rabbit retina by 66%. The results suggest that coupling between members of the OFF α ganglion cell/amacrine cell network is differentially modulated with changing levels of dopamine.