Dopamine’s Effects on Corticostriatal Synapses during Reward-Based Behaviors

Bamford, Nigel S.; Wightman, R. Mark; Sulzer, David

doi:10.1016/j.neuron.2018.01.006

Cited by 120 publications

(104 citation statements)

References 160 publications

(222 reference statements)

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“…If the RPE is positive, additional DA release leads to positive reinforcement of the preceding action; if the error is negative (expected more than received), a pause in DA release leads to negative reinforcement and blocks the action. As a mechanism for this control, DA modulates plasticity of synaptic projections from the cortex to striatal medium spiny neurons (MSNs) [14,15]. As a reflection of the bidirectional DA modulation, there are two types of MSNs.…”

Section: Introductionmentioning

confidence: 99%

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Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

2020

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The basal ganglia (BG) is a collection of nuclei located deep beneath the cerebral cortex that is involved in learning and selection of rewarded actions. Here, we analyzed BG mechanisms that enable these functions. We implemented a rate model of a BG-thalamo-cortical loop and simulated its performance in a standard action selection task. We have shown that potentiation of corticostriatal synapses enables learning of a rewarded option. However, these synapses became redundant later as direct connections between prefrontal and premotor cortices (PFC-PMC) were potentiated by Hebbian learning. After we switched the reward to the previously unrewarded option (reversal), the BG was again responsible for switching to the new option. Due to the potentiated direct cortical connections, the system was biased to the previously rewarded choice, and establishing the new choice required a greater number of trials. Guided by physiological research, we then modified our model to reproduce pathological states of mild Parkinson's and Huntington's diseases. We found that in the Parkinsonian state PMC activity levels become extremely variable, which is caused by oscillations arising in the BG-thalamo-cortical loop. The model reproduced severe impairment of learning and predicted that this is caused by these oscillations as well as a reduced reward prediction signal. In the Huntington state, the potentiation of the PFC-PMC connections produced better learning, but altered BG output disrupted expression of the rewarded choices. This resulted in random switching between rewarded and unrewarded choices resembling an exploratory phase that never ended. Along with other computational studies, our results further reconcile the apparent contradiction between the critical involvement of the BG in execution of previously learned actions and yet no impairment of these actions after BG output is ablated by lesions or deep brain stimulation. We predict that the cortico-BG-thalamo-cortical loop conforms to previously learned choice in healthy conditions, but impedes those choices in disease states.

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Section: Introductionmentioning

confidence: 99%

“…The coordination of activity within the two types of MSNs determines action [21][22][23]. Within the BG loops, synaptic plasticity of corticostriatal projections is a key node in the learning of rewarded choices [6,7,24,15].…”

Section: Introductionmentioning

confidence: 99%

Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

2020

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“…There is evidence that repeated stress exposure disrupts D1 signaling in the prefrontal cortex (Shinohara et al, 2018). Given the complexities of dopamine signaling (different receptor subtypes, brain regional and cell-type-specific differences in dopaminergic regulation, temporal-specific effects during learning) (Bamford et al, 2018), additional study of these agents is needed to determine their place in PTSD therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Stein

Levey

Cheng

et al. 2019

Preprint

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Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to reexperiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 -0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

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“…Nevertheless, it is reasonable to assume that some, if not all, of the above differences in sexual behavior among DAT KO, HET and WT rats may be mediated, at least in part, by an altered interaction between Acb dopamine and glutamic acid. Infact, it is well accepted that: (i) the function of mesolimbic and mesocortical dopaminergic neurons, which play a key role in motivated behavior (Goto and Grace, 2005) and have their cell bodies mainly in the VTA, is finely modulated by the activity of glutamic acid neurons, which originate, although not exclusively, from the PFC and project to the Acb and to the VTA (Carlsson et al, 2001;Carlezon and Thomas, 2009;Beloate and Coolen, 2017;Bamford et al, 2018); (ii) an intact glutamatergic function in the PFC is required for cortical control over the activity of the dopaminergic mesolimbic system to modulate, together with dopamine release, the activity of the GABAergic medium spiny neurons at the level of the Acb and motivated behavior (Carlsson et al, 2001;Kalivas, 2009); and (iii) dopamine and glutamic acid, together with the neuropeptide oxytocin, are key neurotransmitters in the functioning of a complex brain circuit, interconnecting hypothalamic, limbic and cortical areas, involved in both the motivational and performance aspects of male rat sexual behavior (Melis et al, 2007(Melis et al, , 2009(Melis et al, , 2010Succu et al, 2007Succu et al, , 2008Succu et al, , 2011Melis and Argiolas, 2011;Sanna et al, 2017a;Bratzu et al, 2019).…”

Section: Dat Ko Het and Wt Rats Show Different Patterns Of Sexual Bementioning

confidence: 99%

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study

Sanna

Bratzu

Serra

et al. 2020

Front. Behav. Neurosci.

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Central dopamine plays a key role in sexual behavior. Recently, a Dopamine Transporter knockout (DAT KO) rat has been developed, which displays several behavioral dysfunctions that have been related to increased extracellular dopamine levels and altered dopamine turnover secondary to DAT gene silencing. This prompted us to characterize the sexual behavior of these DAT KO rats and their heterozygote (HET) and wild type (WT) counterparts in classical copulatory tests with a sexually receptive female rat and to verify if and how the acquisition of sexual experience changes along five copulatory tests in these rat lines. Extracellular dopamine and glutamic acid concentrations were also measured in the dialysate obtained by intracerebral microdialysis from the nucleus accumbens (Acb) shell of DAT KO, HET and WT rats, which underwent five copulatory tests, when put in the presence of an inaccessible sexually receptive female rat and when copulation was allowed. Markers of neurotropism (BDNF, trkB), neural activation (∆-FosB), functional (Arc and PSA-NCAM) and structural synaptic plasticity (synaptophysin, syntaxin-3, PSD-95) were also measured in the ventral tegmental area (VTA), Acb (shell and core) and medial prefrontal cortex (mPFC) by Western Blot assays. The results indicate that the sexual behavior of DAT KO vs. HET and WT rats shows peculiar differences, mainly due to a more rapid acquisition of stable sexual activity levels and to higher levels of sexual motivation and activity. These differences occurred with differential changes in dopamine and glutamic acid concentrations in Acb dialysates during sexual behavior, with lower increases of dopamine and glutamic acid in DAT KO vs. WT and HET rats, and a lower expression of the markers investigated, mainly in the mPFC, in DAT KO vs. WT rats. Together these findings confirm a key role of dopamine in sexual behavior and provide evidence that the permanently high levels of dopamine triggered by DAT gene silencing cause alterations in both the frontocortical glutamatergic neurons projecting to the Acb and VTA and in the mesolimbic dopaminergic neurons, leading to specific brain regional changes in

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Dopamine’s Effects on Corticostriatal Synapses during Reward-Based Behaviors

Cited by 120 publications

References 160 publications

Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

Basal ganglia role in learning rewarded actions and executing previously learned choices: Healthy and diseased states

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study

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