Dopamine Signaling Research Articles

Meta-analysis of retinal transcriptome profiling studies in animal models of myopia

ObjectiveMyopia prevalence is increasing at alarming rates, yet the underlying mechanistic causes are not understood. Several studies have employed experimental animal models of myopia and transcriptome profiling to identify genes and pathways contributing to myopia. In this study, we determined the retinal transcriptome changes in response to form deprivation in mouse retinas. We then conducted a transcriptome meta-analysis incorporating all publicly available datasets and analyzed how the results related to the genes associated with refractive errors in human genome-wide association studies (GWAS).MethodsForm deprivation was induced in three male C57BL6/J mice from postnatal day 28 (P28) to P42. Retinal gene expression was analyzed with RNA sequencing, followed by differential gene expression analysis with DESeq2 and identification of associated pathways with the Kyoto Encyclopedia of Genes and Genomes (KEGG). A systematic search identified four similar retinal transcriptomics datasets in response to experimental myopia using chicks or mice. The five studies underwent transcriptome meta-analyses to determine retinal gene expression changes and associated pathways. The results were compared with genes associated with human myopia.ResultsDifferential gene expression analysis of form-deprived mouse retinas revealed 235 significantly altered transcripts, implicating the BMP2 signaling pathway and circadian rhythms, among others. Transcriptome-wide meta-analyses of experimental myopia datasets found 427 differentially expressed genes in the mouse model and 1,110 in the chick model, with limited gene overlap between species. Pathway analysis of these two gene sets implicated TGF-beta signaling and circadian rhythm pathways in both mouse and chick retinas. Some pathways associated only with mouse retinal changes included dopamine signaling and HIF-1 signaling pathway, whereas glucagon signaling was only associated with gene changes in chick retinas. The follistatin gene changed in both mouse and chick retinas and has also been implicated in human myopia. TGF-beta signaling pathway and circadian entrainment processes were associated with myopia in mice, chicks, and humans.ConclusionThis study highlights the power of combining datasets to enhance statistical power and identify robust gene expression changes across different experimental animal models and conditions. The data supports other experimental evidence that TGF-beta signaling pathway and circadian rhythms are involved in myopic eye growth.

Sequence termination cues drive habits via dopamine-mediated credit assignment.

Mesolimbic dopamine (DA) neurons are central to sequence learning and habit formation. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to investigate how sequence initiation and termination cues influence DA-driven behavioral strategies and learning. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in mediating credit assignment and driving the development of habitual action sequence execution.

Gestational stress disrupts dopamine and oxytocin signaling in the postpartum reward system of rats: implications for mood, motivation and mothering

Postpartum depression (PPD) affects up to 20% of new mothers and has adverse consequences for the well-being of both mother and child. Exposure to stress during pregnancy as well as dysregulation in the mesolimbic dopamine (DA) reward system and its upstream modulator oxytocin (OT) have been independently linked to PPD. However, no studies have directly examined DA or OT signaling in the postpartum brain after gestational stress. Here we employed a chronic variable stress procedure during pregnancy and evaluated behavioral measures of mood and reward along with assessments of DA and OT signaling in postpartum rats. Our results show that gestational stress induced postpartum depressive-like and anxiety-like behavior in addition to producing reward-related deficits including anhedonia, impaired maternal care, and reduced maternal motivation. Consistent with a hypodopaminergic state, histological analysis revealed reduced expression of tyrosine hydroxylase in the NAc shell and core as well as reduced expression of the dopamine transporter and dopamine D2 receptor in the NAc shell of postpartum females exposed to gestational stress. A reduction in accumbal DA content as determined by liquid chromatography-mass spectrometry was also observed in gestationally-stressed dams. Lastly, we assessed mRNA expression of OT and OT receptors (OTR) and found that gestational stress increased OT expression in the hypothalamus but reduced OTR expression in the postpartum ventral tegmental area (VTA), a target of hypothalamic OT neurons. In the VTA, a reduction in OT-immunoreactive fibers following gestational stress was also seen. Taken together, these data demonstrate that the DA and OT systems within the postpartum reward circuit are sensitive to gestational stress and suggest that mood and maternal disruptions in PPD may arise from dysfunctional oxytocinergic regulation of the dopaminergic reward system.

G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis.

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

DRD4 Interacts with TGF-β Receptors to Drive Colorectal Cancer Metastasis Independently of Dopamine Signaling Pathway.

The functional and pharmacological significance of dopamine receptor D4 (DRD4)in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy.

Glial Derived Neurotrophic Factor and Schizophrenia Spectrum Disorders: A Scoping Review.

Psychotic disorders, characterized by altered brain function, significantly impair reality perception. The neurodevelopmental hypothesis suggests these disorders originate from early brain development disruptions. Glial-derived neurotrophic factor (GDNF) is crucial for neuronal survival and differentiation, especially in dopaminergic neurons, and shows promise in neurodegenerative and neuropsychiatric conditions. This scoping review aims to examine the role of GDNF in schizophrenia spectrum disorders and substance-induced psychoses, integrating knowledge on the neurobiological mechanisms and therapeutic potential of GDNF. A comprehensive literature search was conducted using PubMed and Scopus databases from January 2001 onwards. Data extraction focused on GDNF levels, cognitive function, antipsychotic treatment effects, and genetic studies. The review included 25 studies (18 human, 7 animal). While some studies demonstrated inconsistent results regarding GDNF serum levels in schizophrenic patients, the majority reported correlations between GDNF levels and cognitive functions. Animal studies underscored GDNF's role in stress response, drug-induced neurotoxicity, and dopamine signaling abnormalities. Genetic studies revealed potential associations between GDNF gene polymorphisms and schizophrenia susceptibility, though findings were mixed. GDNF plays a significant role in cognitive functions and neuroprotection in schizophrenia. The variability in study results underscores the complexity of GDNF's involvement. The therapeutic potential of GDNF in psychotic disorders remains unclear, necessitating further research to clarify its efficacy and safety. This review emphasizes the importance of integrated biomarker strategies, gene therapy approaches, and precision medicine in advancing the understanding and treatment of psychotic disorders.

Dopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA-dependent behaviors.

The dopamine (DA) transporter (DAT) is a major determinant of DAergic neurotransmission, and is a primary target for addictive and therapeutic psychostimulants. Evidence accumulated over decades in cell lines and invitro preparations revealed that DAT function is acutely regulated by membrane trafficking. Many of these findings have recently been validated invivo and insitu, and several behavioral and physiological findings raise the possibility that regulated DAT trafficking may impact DA signaling and DA-dependent behaviors. Here we review key DAT trafficking findings across multiple systems, and discuss the cellular mechanisms that mediate DAT trafficking, as well as the endogenous receptors and signaling pathways that drive regulated DAT trafficking. We additionally discuss recent findings that DAT trafficking dysfunction correlates to perturbations in DA signaling and DA-dependent behaviors.

Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors.

Dopamine (DA) release in striatal circuits, including the nucleus accumbens medial shell (mNAcSh), tracks separable features of reward like motivation and reinforcement. However, the cellular and circuit mechanisms by which DA receptors transform DA release into distinct constructs of reward remain unclear. Here we show that DA D3 receptor (D3R) signaling in the mNAcSh drives motivated behavior in mice by regulating local microcircuits. Furthermore, D3Rs coexpress with DA D1 receptors, which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report nonoverlapping physiological actions of D3R and DA D1 receptor signaling in mNAcSh neurons. Our results establish a fundamental framework wherein DA signaling within the same nucleus accumbens cell type is physiologically compartmentalized via actions on distinct DA receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors relevant to the etiology of neuropsychiatric disorders.

Iron deficiency negatively affects behavioral measures of learning, indirect neural measures of dopamine, and neural efficiency.

Iron deficiency (ID) is the most prevalent nutrient deficiency in the world, with a growing literature documenting the negative effects of ID on perception, attention, and memory. Animal models of ID suggest that dysregulation of dopamine is responsible for the deficits in memory. However, evidence that ID affects dopamine in humans is extremely limited. We report the results of a study involving college-aged women with and without ID learning two different category structures - a rule-based and an information-integration structure - selected based on the putative differential role of dopamine in learning these two structures. ID non-anemic (IDNA) and iron-sufficient (IS) women completed 1200 learning trials for each structure. EEG was collected to assess the effects of ID on features affected by dopaminergic state: error-related negativity (ERN) and positivity (Pe), feedback-related negativity (FRN), and task-related blink rate. In addition, we examined the EEG data for dynamics distinguishing IDNA from IS women, including a measure of neural efficiency. Both groups of women were able to learn both structures. However, IDNA women were initially slower and less accurate than IS women, specifically for the rule-based structure. There were large and persistent group differences in brain dynamics and neural efficiency measures. The results are discussed with respect to the selective impact of ID on initial rule-based learning and the persistent effect of ID on dopamine signaling and energetic efficiency.

Lower density of calretinin-immunopositive neurons in the putamen of subjects with schizophrenia.

Schizophrenia (SCH) is a chronic and serious mental illness which puts an enormous burden on the individual, families, and society. It is well established that altered dopamine signaling and excitatory-inhibitory imbalance contributes to the symptoms of schizophrenia. Recent neuroimaging and histological studies suggest that the striatum is a key area involved in SCH, however, our knowledge of how specific cell neuronal subtypes of certain subcortical structures may be impaired is incomplete. To this date, no detailed investigation of the putamen has ever been published regarding neuroanatomical changes in SCH. Here we tested whether the density of calretinin immunopositive (CR+) neurons and DARPP32+ neurons is altered in the putamen of patients with SCH. We used immunohistochemistry to reveal CR+ and DARPP32+ neurons in six samples from patients with SCH and six age- and gender-matched control subjects. In line with previous studies, we detected small, medium, and large CR+ neurons. The density of small CR+ neurons was significantly lower in SCH (p = 0.0076). Medium and large CR+ and DARPP32+ neuronal density was not significantly different between groups. The present study substantiates previous results showing significantly lower density of small CR+ interneurons in the caudate nucleus in samples from patients with schizophrenia, highlighting the involvement of the striatum in the disorder. Our results warrant further studies focusing on the role of CR+ interneurons in the regulation of information processing in the fronto-striatal networks, evidently key structures in schizophrenia.

Striosome circuitry stimulation inhibits striatal dopamine release and locomotion.

The mammalian striatum is divided into two types of anatomical structures: the island-like, mu opioid receptor (MOR)-rich striosome compartment and the surrounding matrix compartment. Both compartments have two types of spiny projection neurons (SPNs), dopamine receptor D1 (D1R)-expressing direct pathway SPNs (dSPNs) and dopamine receptor D2 (D2R)-expressing indirect pathway SPNs. These compartmentalized structures have distinct roles in the development of movement disorders, although the functional significance of the striosome compartment for motor control and dopamine regulation remains to be elucidated. The aim of this study was to explore the roles of striosome in locomotion and dopamine dynamics in freely moving mice. We targeted striosomal MOR-expressing neurons with male MOR-CreER mice, which express tamoxifen-inducible Cre recombinase under MOR promoter, and Cre-dependent adeno-associated virus vector. The targeted neuronal population consisted mainly of dSPNs. We found that the Gq-coupled designer receptor exclusively activated by designer drugs (DREADD)-based chemogenetic stimulation of striatal MOR-expressing neurons caused a decrease in the number of contralateral rotations and total distance traveled. Wireless fiber photometry with a genetically-encoded dopamine sensor revealed that chemogenetic stimulation of striatal MOR-expressing neurons suppressed dopamine signals in the dorsal striatum of freely moving mice. Furthermore, the decrease in mean dopamine signal and the reduction of transients were associated with ipsilateral rotational shift and decrease of average speed, respectively. Thus, a subset of striosomal dSPNs inhibits contralateral rotation, locomotion, and dopamine release in contrast to the role of pan-dSPNs. Our results suggest that striatal MOR-expressing neurons have distinct roles in motor control and dopamine regulation.Significance of statement The striatum plays a crucial role in motor control, and it consists of two anatomical compartments: mu opioid receptor (MOR)-rich striosomes and the surrounding matrix. The striosome sends efferent inhibitions to midbrain dopaminergic neurons, but it remains unknown whether striosomes are involved in motor control and dopamine regulation in behaving animals. We used MOR-expression based targeting, chemogenetics and wireless fiber photometry with a genetically-encoded dopamine sensor, and we found that chemogenetic stimulation of striosomal MOR-expressing neurons inhibits contralateral rotations, locomotion, and dopamine release in the dorsal striatum. The rotational shift and the locomotion decrease might be differently associated with dopamine dynamics. This study provides compelling evidence that striosomal MOR-expressing neurons inhibit motor behavior and dopamine release in freely moving animals.

Developmental and Adult Striatal Patterning of Nociceptin Ligand Marks Striosomal Population With Direct Dopamine Projections.

Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting the early developmental expression of Pnoc. In the ventral striatum, Pnoc expression in the nucleus accumbens core was grouped in clusters akin to the distribution found in striosomes. We found that PnoctdTomato reporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projection neurons for their direct innervation of midbrain dopamine neurons. These findings provide a new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striato-nigral circuits.

Oxytocin Reduces Methylphenidate-Induced Dorsal Striatal Dopamine Release in Male Rhesus Macaques.

Oxytocin is being evaluated as a potential treatment for psychostimulant use disorders. It is unknown what effect oxytocin has on dopamine signaling in response to psychostimulants in brain regions such as the striatum where oxytocin and dopamine interact to process natural rewards. We investigated the effect of oxytocin on striatal dopamine release stimulated by methylphenidate whose mechanism of action is analogous to that of cocaine. We conducted an [11C] raclopride positron emission tomography study to assess striatal dopamine release in male rhesus macaques treated with oxytocin (80 IU) (administered via the intranasal [N = 5] and intravenous [N = 6] routes) followed by methylphenidate/[11C] raclopride. Oxytocin delivered by both routes significantly reduced methylphenidate-stimulated dopamine release in the dorsal striatum (caudate/putamen). These effects were, in part, evidenced by a reduction in dorsal striatal [11C] raclopride binding potential (increased dopamine release) following oxytocin administration. The results provide translational and mechanistic evidence for the potential role of oxytocin as a treatment for psychostimulant use disorders.

Dysbindin-1 Mutation Alters Prefrontal Cortex Extracellular Glutamate and Dopamine In Vivo.

Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content.

Opponent control of reinforcement by striatal dopamine and serotonin.

The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning1-8. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations9-14. However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a mouse model enabling simultaneous genetic access to the brain's DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signaling and decrease 5HT signaling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioral deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive acquisition of new associations and supported reinforcement more potently than either manipulation alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

Dopamine release and dopamine-related gene expression in the amygdala are modulated by the gastrin-releasing peptide in opposite directions during stress-enhanced fear learning and extinction.

Fear extinction leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism's survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.

Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes.

Astrocytes are increasingly appreciated to possess underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a "soma-to-soma" satellite-like configuration not typically observed for other striatal neurons. We find that transient depolarization of astrocytes in mouse striatum reversibly regulates ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling.

FGF21 acts in the brain to drive macronutrient-specific changes in behavioral motivation and brain reward signaling

ObjectiveDietary protein restriction induces adaptive changes in food preference, increasing protein consumption over carbohydrates or fat. We investigated whether motivation and reward signaling underpin these preferences. Methods and ResultsIn an operant task, protein-restricted male mice responded more for liquid protein rewards, but not carbohydrate, fat, or sweet rewards compared to non-restricted mice. When the number of responses required to access protein reward varied, protein-restricted mice exhibited higher operant responses at moderate to high response requirements. The protein restriction-induced increase in operant responding for protein was absent in Fgf21-KO mice and mice with neuron-specific deletion of the FGF21 co-receptor beta-Klotho (KlbCam2ka). Fiber photometry recording of VTA dopamine neurons revealed that oral delivery of maltodextrin triggered a larger dopamine neuron activation than casein in control diet-fed mice, while casein triggered a larger activation in low-protein diet-fed mice. This restriction-induced shift in nutrient-specific VTA dopamine signaling was lost in Fgf21-KO mice. ConclusionThese data suggest that the increased FGF21 during protein restriction acts in the brain to induce a protein-specific appetite by specifically enhancing the reward value of protein-containing foods and the motivation to consume them.

Dynamic Changes in Chloride Homeostasis Coordinate Midbrain Inhibitory Network Activity during Reward Learning.

The ability to associate environmental stimuli with positive outcomes is a fundamental form of learning. While extensive research has focused on the response profiles of midbrain dopamine neurons during associative learning, less is known about learning-mediated changes in the afferents that shape their responses. We demonstrate that during critical phases of learning, anion homeostasis in midbrain GABA neurons - a primary source of input to dopamine neurons - is disrupted due to downregulation of the chloride transporter KCC2. This alteration in GABA neurons preferentially impacted lateral mesoaccumbal dopamine pathways and was not observed after learning was established. At the network level, learning-mediated KCC2 downregulation was associated with enhanced synchronization between individual GABA neurons and increased dopamine responses to reward-related stimuli. Conversely, enhancing KCC2 function during learning reduced GABA synchronization, diminished relevant dopamine signaling, and prevented cue-reward associations. Thus, circuit-specific adaptations in midbrain GABA neurons are crucial for forming new reward-related behaviors.

The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models.

Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review evidence collected during the past 40-plus years supporting the role of dopamine dysfunction in attention deficit hyperactivity disorder (ADHD). We recapitulate the basic components of dopaminergic signaling in the central nervous system, focusing on core enzymes, transporters and receptors involved in monoaminergic functions, particularly in striatal and cortical regions. We summarize key human brain imaging and genetic studies reporting associations between dopaminergic neurotransmission and behavioral traits, with an emphasis on ADHD. We also consider ADHD in the context of animal models and single gene, metabolic, and neurological disorders with established dysfunction of the dopaminergic system. Examining the evidence in this way leads us to conclude that there is evidence for the involvement of dopamine but limited evidence for a hypo-dopaminergic state per se as a key component of ADHD. We propose a path forward to increase our understanding of dopamine signaling in human behavioral traits and disorders that should particularly focus on its role in clinical subgroups, during brain development and how it interacts with other neurotransmitter systems.