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Thus, both innate and learned responses to sodium are intimately connected with the physiological state of the animal. Moreover, the findings implicate an important role of VTA-NAc phasic dopamine in guiding goal-directed behaviors based on perturbations in body fluid homeostasis.
Based on the work described above, changes in physiological state and homeostatic perturbation have a key role in modulating mesolimbic pathways and their relevant behavioral outputs. What remains unclear are the gating mechanisms that 1 provide information regarding physiological state to the mesolimbic system and 2 how mesolimbic pathways integrate and relay this information.
Fortunately, there are many investigations that provide insight into the mechanisms linking peripheral signals e. Receptors for a multitude of feeding related hormones are expressed throughout the brain including key nodes within the mesolimbic pathway 77 , — This provides one potential and relatively straightforward mechanism through which perturbations in homeostasis might directly influence mesolimbic physiology.
Moreover, GLP-1R action within the VTA can alter phasic dopamine signaling as, in our laboratory, we demonstrated that LiCl-induced reductions in stimulated phasic dopamine release can be attenuated by GLP-1R blockade 58 and that ventricular injections of the GLP-1R agonist, exendin-4, can reduce cocaine-induced phasic dopamine signaling in the NAc core These effects appear to be due, in part, to altered excitatory drive onto dopamine cell bodies as GLP-1R activation does not alter evoked NAc phasic dopamine release as measured in ex vivo brain slices Other satiety hormones, including amylin and leptin, which have effects on food intake and related behaviors, are also capable of modulating phasic dopamine signaling.
Indeed, in addition to VTA amylin receptor activation reducing food intake and food motivated behaviors, amylin receptor signaling in the VTA also reduces NAc core phasic dopamine release It remains possible, though, that some of the effects of amylin may be either indirect, through action in the area postrema or via the calcitonin receptor VTA amylin signaling also synergistically acts with leptin receptor signaling, where combined activation of receptors for these hormones in the VTA produces weight loss and hypophagia Leptin receptor signaling in the VTA, similar to the other satiety peptides described above, can independently control energy balance and food motivated behaviors.
Intra-VTA administration of leptin reduces food intake, while knockdown of VTA leptin receptors results in hyperphagia and heightened sensitivity to palatable foods The sustained weight loss from VTA manipulation is yet another example of overlap between the role of the VTA in homeostatic and reward-related functions.
Interestingly, leptin and insulin signaling in the VTA can also reduce excitatory synaptic transmission on to dopamine neurons, attenuate VTA dopamine concentration, and reduce food motivated behaviors — Leptin can also exert its effects on cocaine-seeking behaviors via attenuation of cocaine-induced increases in NAc dopamine levels and also reduces dopamine neuron activity Overall, these data demonstrate that leptin not only has an impact on mesolimbic pathways but is also physiologically critical for the expression of goal-directed behaviors for either nutritive or non-nutritive substances and appropriate functioning of phasic dopamine signaling.
However, in the case of insulin, there are a few inconsistencies. In response to insulin, while some have described attenuated VTA dopamine concentration and reduced excitatory synaptic transmission — , others have demonstrated increases in dopamine neuron activity and striatal dopamine release , In light of this, the net effect of insulin on phasic dopamine activity remains unclear.
One intriguing proposal is that local NAc circuits have a critical role in modulating insulin-mediated phasic dopamine signaling This represents a key mechanism through which VTA and NAc dopamine signaling can independently use homeostatic signals to regulate state-dependent goal-directed behaviors.
Like satiety hormones, peripheral hunger signals can also directly act within VTA-NAc dopamine systems. Physiologically, ghrelin action in the VTA increases dopamine neuronal firing, synaptic plasticity, and NAc dopamine turnover Pharmacological manipulations have demonstrated that intra-VTA and NAc shell delivery of ghrelin can increase food intake, however, only VTA ghrelin receptor signaling is effective in increasing food motivated behaviors i.
One possible explanation for this is divergent circuitry from the VTA to other feeding relevant brain regions e. Our laboratory has explored the effects of central ghrelin signaling on phasic dopamine release in the NAc.
In awake, behaving ad libitum fed rats, delivery and consumption of sugar pellets reliably evoked modest phasic dopamine release in the NAc core; this release was significantly greater in food-restricted rats. Importantly, the effect of food restriction was recapitulated in ad libitum fed rats that were given intracerebroventricular ghrelin during the recording session.
Interestingly, this effect was recapitulated by delivery of ghrelin to the LH targeting orexin positive neurons but not the VTA directly —supporting multi-synaptic processes in driving phasic dopamine signaling.
Furthermore, ghrelin's ability to potentiate phasic dopamine release extends beyond primary food reward, as central administration of ghrelin can also increase NAc phasic dopamine responses to food-predictive cues Thus, by integrating hormonal signals directly within VTA-NAc pathways, mesolimbic dopamine signaling can relay information relating to both hunger and satiety states to then guide goal-directed behaviors.
Besides the role of hormonal signaling within mesolimbic dopamine pathways, other post-ingestive consequences of nutrient consumption can impact central neural substrates and subsequently guide goal-directed behaviors. In regards to the neural correlates that mediate caloric sensing and cues associated with calories, mesolimbic dopamine neurons again arise as potential nodes that integrate and relay post-ingestive information.
Several investigations have determined that animals can, independently of taste, use the post-ingestive consequences of nutrient consumption e. For example, while animals are able to generate preferences for both sucrose and non-nutritive saccharin in comparison to water, sucrose preference is substantially greater than saccharin even when matched for sweetness.
This is further emphasized in operant conditioning tasks, where animals are more inclined to lever press for nutritive substances e. These results further suggest that motivated behaviors can occur independently of hedonic value, although hedonic value certainly acts synergistically with nutritional value Furthermore, using fast-scan cyclic-voltammetry, this study revealed greater phasic dopamine signals in the NAc core to delivery of sucrose pellets than to saccharin pellets, suggesting that mesolimbic phasic dopamine is capable of encoding the nutritive value of substances This is further supported by studies that examined cued associations with nutritive or non-nutritive rewards.
From our laboratory, in rats conditioned to associate cues with the delivery of either sucrose or saccharin pellets, we found that sucrose cues evoked greater phasic dopamine release in the NAc core, relative to saccharin cues.
Importantly, this difference was greatest when sucrose and saccharin were presented on alternate days during conditioning—giving rats the opportunity to distinguish between post-ingestive consequences of each type of reward. When the nutritive value of these rewards was masked by presenting saccharin and sucrose pellets within the same session, the attenuation of phasic dopamine release to the saccharin cues, relative to sucrose cues, was reduced although, interestingly, was not abolished , Overall, these data suggest that while the encoding of hedonic taste value plays a role in modulating phasic dopamine signaling, nutritive value of rewards also contributes strongly to these processes.
Interestingly, mesolimbic dopamine can be highly sensitive to the precise caloric content of nutrients. Fat, similar to sucrose and glucose, also elicits post-ingestive feedback mechanisms that influence goal-directed behaviors , — When fat is delivered intragastrically, dorsal striatal dopamine levels increase in parallel with increasing caloric density of fat infusions, and dopamine receptor blockade impairs an animal's ability to regulate caloric intake These data suggest that mesolimbic dopamine signaling not only regulates caloric sensing, but also relays a signal reflecting the magnitude of caloric content.
The mechanisms regulating caloric sensing and hormonal regulation of energy balance, while intertwined, can also exhibit dissociable processes. In experiments involving intragastric infusions of glucose, disruption of glucose metabolism with intravenous 2-DG was shown to reduce striatal dopamine levels. Interestingly, this reduction was rescued with subsequent intravenous glucose administration In a separate study, delivery of low concentrations of glucose into hepatic-portal vein was shown to increase spontaneous phasic dopamine release events in the NAc shell Thus, in addition to peripheral hormonal signals, which relay homeostatic state and taste information encoding hedonic value, peripheral nutrient sensing and post-ingestive feedback signals are also critical mechanisms that regulate mesolimbic dopamine signaling in response to homeostatic perturbation.
The data described above have covered dopamine signaling in response to calories in both the dorsal and ventral striatum—brain regions that have been previously attributed to dissociable functions in regards to motivated behaviors Indeed, recent evidence has suggested that dorsal and ventral striatal dopamine pathways are differentially modulated by caloric content and hedonic value.
As such, intake of non-nutritive sucralose was shown to increase ventral striatal dopamine levels, however, increases in dopamine within the dorsal striatum only occurred when sucralose intake was paired with intragastric glucose.
Moreover, when intragastric glucose infusions were paired with the taste of a bitter compound, ventral striatal dopamine was unresponsive, relative to baseline, while dorsal striatal dopamine levels were augmented Taken together, these results provide evidence for separate striatal circuits that regulate hedonic value or post-ingestive reinforcement.
However, questions remain regarding whether hedonic value and caloric value are processed either through distinct dorsal vs. Regional specificity of phasic dopamine signals remains a subject of intense study — While physiological state information can be relayed to the mesolimbic system directly via hormones, the VTA and NAc also receive extensive neuronal projections from a multitude of neural substrates that are involved in processing homeostatic information.
This provides an alternative, yet complementary, mechanism through which physiological state information is integrated prior to being transmitted to the mesolimbic dopamine system.
Hindbrain neural processes are capable of modulating goal-oriented behaviors and reward 83 , 84 , Thus, it is unsurprising that homeostatic information that is relayed to hindbrain neural substrates can be transmitted to mesolimbic dopamine pathways.
These data suggest that, besides direct homeostatic signaling to mesolimbic circuitry, these signals can be initially gated by hindbrain processes before being relayed to the mesolimbic circuits. Further support for this hypothesis can be observed in animals with lesions to the area postrema AP and parabrachial nucleus PBN - while amylin receptor activation can reduce VTA stimulated dopamine release in the NAc in control animals, these effects are abolished in animals with either AP or PBN lesions Brainstem subregions that regulate body fluid homeostasis also have projections to the mesolimbic pathway.
Besides hindbrain projections, the VTA also receives extensive input from midbrain substrates that regulate homeostatic processes. In particular, the lateral dorsal tegmental area LDTg projections to the VTA , have been identified as one pathway that regulates homeostatic functions and goal-directed behaviors. Interestingly, animals can be trained to self-administer optogenetic activation of LDTg inputs to the VTA , which in turn increases NAc dopamine levels Additionally, excitation of cholinergic or glutamatergic LDTg input to the VTA produces conditioned place preference for opioids Overall, these data provide support for LDTg to VTA pathways in modulating reward, however, whether homeostatic changes can mediate this pathway remains understudied.
Nonetheless, the LDTg is anatomically poised to use homeostatic signals. Recent data have also demonstrated that GLP-1 and amylin receptor activation in the LDTg reduces food intake and motivated behaviors. Collectively, midbrain LDTg input to the VTA is critical for VTA function, and this system reflects yet another parallel pathway through which homeostasis and reward interact.
Other midbrain inputs to the VTA, including the pedunculopontine tegmental nucleus PPTg can modulate goal-directed behaviors and putative homeostatic functions. For example, the PPTg sends cholinergic and glutamatergic input to the VTA — , modulates burst firing of VTA neurons , and interacts with the VTA, along with other limbic structures, to regulate reinstatement of cocaine seeking In the context of homeostasis, others have demonstrated that PPTg lesions block food conditioned place preference in food-sated, but not food-deprived rats Moreover, melanin-concentrating hormone MCH and orexin producing neurons from the LHA send projections to the PPTg , although the role of this pathway in modulating energy balance is unknown.
Thus, while the PPTg appears to have putative roles in regulating homeostatic balance and goal-directed behaviors, the precise interactions between PPTg, homeostatic perturbations, and phasic dopamine signaling remains to be determined. Hypothalamic nuclei in the forebrain, as we have briefly discussed, consist of classic homeostatic neural regulators.
In parallel with hindbrain and midbrain pathways, hypothalamic brain regions, in particular the lateral hypothalamic area LHA , send direct and reciprocal projections to the 3 , — and provide another set of circuits through which homeostatic signals can be relayed to the mesolimbic dopamine system. Interestingly, animals will self-administer photostimulation of LHA-VTA pathways, an effect that is mediated by neurotensin transmission Polysynaptic pathways to the NAc can also modulate reward seeking.
For example, LHA CART cocaine and amphetamine regulated transcript neurons that project to the paraventricular thalamic nucleus PVT promote reward behaviors, which can then be attenuated by glutamate receptor blockade in the NAc shell In the context of homeostatic regulation, there have been some efforts to delineate the relationship between hormonal signals, the LHA, and VTA dopamine signaling. The LHA contains a subpopulation of neurons that produce orexin, a neuropeptide that interacts with feeding hormones and drugs of abuse 80 , — , which then project to many sites throughout the brain, the VTA among them.
It has been demonstrated in vitro that leptin administration can reduce excitatory synaptic strength between LHA orexin neurons and the VTA and that these effects can be attenuated by fasting or high-fat diet induced obesity Additionally, energy balance can be regulated through LHA neurotensin neurons that also express leptin receptors.
These in turn modulate local LHA orexin neurons that subsequently impact mesolimbic pathways Finally, we have demonstrated in our laboratory that the hyperphagic effects of central ghrelin administration can be blunted by intra-VTA administration of orexin receptor antagonist and that ghrelin injected directly into LHA recapitulates the effect of ICV ghrelin on phasic dopamine signaling whereas, interestingly, intra-VTA ghrelin does not Neurons in the LHA are also sensitive to levels of circulating nutrients and this may be a route by which nutritional value is relayed to mesolimbic circuitry — These neurons project to VTA and optogenetic activation of their terminals biases preference for the non-nutritive sweetener, sucralose, relative to sucrose.
Interestingly, co-activation of these terminals while mice are drinking water is not sufficient to shift their preference away from sucrose, indicating that taste is involved and is presumably integrated with nutritive value as relayed by MCH neuron activation. Collectively, the data described above are a prime example of how reward-seeking is modulated by changes to physiological state and, moreover, show how hypothalamic to VTA circuits can act in concert with hindbrain and midbrain VTA pathways to dynamically regulate homeostatic responses and goal-directed behaviors.
Growing evidence now supports forebrain structures involved in executive functions such as learning, memory, and decision making, as sites for homeostatic signaling 14 , — Of particular interest are pathways originating from the ventral subregion of the hippocampus vHP , which have been shown to interact with phasic dopamine signaling as well as to integrate homeostatic signals — For example, ghrelin administration to the vHP increases food intake and reward seeking and increases phosphorylated tyrosine hydroxylase within the NAc The vHP also has the capability of bidirectionally modulating feeding behaviors, as GLP-1R signaling in the vHP potently reduces food intake and motivated behaviors The mPFC to NAc projections have been implicated in a variety of phasic dopamine-related functions — and mPFC dopamine signaling has been shown to have a role in modulating energy balance and feeding Together, these data provide another polysynaptic pathway e.
Overall, these data emphasize the notion that pathways that regulate homeostasis and goal-directed behaviors are remarkably complex, and the degree to which information regarding physiological state is relayed to mesolimbic dopamine pathways is not limited to peripheral, hindbrain, or midbrain input.
In the current review, we have emphasized the notion that there is substantial overlap between homeostatic and reward-related neural processes. More specifically, existing data support complex, dynamic, and parallel neural pathways that integrate physiological state and goal-directed behaviors.
Accordingly, mesolimbic phasic dopamine signaling represents one of many central mechanisms through which these integrative processes can occur. However, many questions remain to be addressed. First, the intricacies between phasic burst firing of VTA dopamine cell bodies and terminal dopamine release in the NAc are under evaluation.
While we have described heterogeneity of VTA dopamine neurons in processing positive vs. Of course, while VTA dopamine neuron activity and phasic burst firing of VTA neurons robustly mediates terminal dopamine release and reuptake 22 , , several investigations have proposed the notion that NAc neurons are capable of modulating terminal release of dopamine independently of VTA cell bodies 24 — For example, optogenetic activation of NAc cholinergic interneurons increases extracellular dopamine 25 , 26 that is in turn modulated by the endocannabinoid system and prefrontal cortical afferents to the NAc In the context of homeostatic modulation of phasic dopamine signaling, we have briefly described the effects of insulin on NAc dopamine release.
Data from Stouffer and colleagues have emphasized the role of cholinergic interneurons which express insulin receptors in modulating the insulin-mediated increases in dopamine levels within the striatum Collectively, the possibility of local NAc circuitry and NAc input from other brain regions in modulating dopamine release should be a focal topic in conjunction with perturbations in homeostasis.
Next, we have described the ability of phasic dopamine signaling to respond to a variety of different perturbations to homeostasis, however, whether the responses of the mesolimbic dopamine system to varying physiological states utilizes overlapping or distinct output pathways is unknown. Given the variety of inputs to the VTA, as we have described above, it seems highly likely that these inputs are capable of engaging distinct subpopulations of VTA neurons whose signals are subsequently integrated to generate a specific behavioral outcome.
For example, in the case of feeding and energy balance, it would be enlightening to determine whether the receptors for feeding hormones are co-expressed on the same neuronal populations within the VTA and how anorexigenic and orexigenic peptides interact through local VTA circuits to impact phasic dopamine signaling.
In a similar vein, the degree to which perturbations in body fluid homeostasis can impact mechanisms regulating energy balance at the level of the VTA should also be examined. Eating and drinking are intimately linked and it is well known that eating stimulates thirst and dehydration induces anorexia [excellently reviewed in ]. Moreover, temporal differences in signaling pathways between this mixture of hormones might also affect these interactions.
Indeed, what is left to be reconciled is the slow temporal action of peripheral hormone or nutrient signaling to the brain, relative to the rapid subsecond actions of phasic dopamine signaling. In light of the data presented here, the endogenous relevance of phasic dopamine signaling in regulating behavioral responses to homeostatic perturbations requires further study.
The question that remains, however, is how the robust influence of homeostatic perturbation on phasic dopamine signaling subsequently impacts particular behavioral components that are related to motivation and goal direction. One possibility is that homeostatic need states tune phasic dopamine signaling to engage appetitive behaviors toward stimuli that are relevant for the need state.
For example, in a sodium deplete state, this physiological state might tune phasic dopamine signaling to engage appetitive behaviors for obtaining sodium, while responses for food reward are attenuated.
Whether VTA-NAc pathways are physiologically relevant for these behavioral outputs remains to be seen. Thus, for future studies, researchers might use loss-of-function experiments e. Finally, the interaction between sex differences, homeostasis, and phasic dopamine signaling requires extensive examination.
Several recent studies have demonstrated that the effects of central homeostatic signaling are sex dimorphic. For example, female rats have higher levels of LHA ghrelin receptor expression than males, and acute blockade of LHA ghrelin receptors in females, but not males, reduces food intake, body weight, and food seeking behaviors Central GLP-1R activity also reveals sex dimorphism, where broad activation of GLP-1Rs results in greater suppression in food motivated behaviors in female compared to male rats along with interactions with estrogen signaling Interestingly, these results appear to vary depending on brain region, as LHA GLP-1R knockdown or blockade increases food motivation only in male rats Examination of sex differences in body fluid homeostasis are also in progress.
Recent studies have revealed an effect of sex on thirst, including increased water intake in male rats compared to female rats in response to angiotensin II , a lack of desensitization to repeated angiotensin II administration in female rats , and interactions of thirst and estrogens Thus, future work should examine whether these sex dimorphisms in homeostatic regulation are reflected in mesolimbic phasic dopamine signaling.
While questions remain, a putative mechanism arises whereby neurons in the VTA are readily able to burst fire in response to homeostatic perturbation and the presence of state-relevant stimuli e. The result of the phasic increase could be to alter ongoing NAc activity as well as plasticity in the service of guiding motivated behaviors. Future research conducted with a special emphasis on the impact of physiological state on mesolimbic dopamine signaling will be critical in furthering our understanding of maladaptive behaviors with the eventual goal of effectively treating prominent health issues such as obesity and drug addiction.
TH generated drafts. JM and MR provided critical discussion, edits and comments. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Margules DL, Olds J. Science —5. Weingarten HP. Conditioned cues elicit feeding in sated rats: a role for learning in meal initiation.
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J Neurosci. The need to feed: homeostatic and hedonic control of eating. Neuron — Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? References: Adinoff, B. Neurobiologic Processes in Drug Reward and Addiction. Harvard Review of Psychiatry, 12 6 , — Comparison of the neuroprotective potential of Mucuna pruriens seed extract with estrogen in 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP -induced PD mice model [Abstract].
Neurochemistry International, 65, Springer India. Nathan Bridges. Stay up to date with sanesco. Other Related Blogs. Cognitive Health and Your Neurotransmitters. July 27, Blog , Focus , Nutritional Therapies 7 minute read.
Healthy Cognitive Function in Children. September 16, Blog , Focus , NeuroLab 5 minutes. Follow Us. Get Connected. Get Setup and start today. The VTA is the site of dopaminergic neurons, which tell the organism whether an environmental stimulus natural reward, drug of abuse, stress is rewarding or aversive.
This region mediates the rewarding effects of natural rewards and drugs of abuse. The amygdala is particularly important for conditioned forms of learning. It helps an organism establish associations between environmental cues and whether or not that particular experience was rewarding or aversive, for example, remembering what accompanied finding food or fleeing a predator.
It also interacts with the VTA-NAc pathway to determine the rewarding or aversive value of an environmental stimulus natural reward, drug of abuse, stress.
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