Dopamine promotes aggression in mice via ventral tegmental area to lateral septum projections

Mahadevia, Darshini; Saha, Rinki; Manganaro, Alessia; Chuhma, Nao; Ziolkowski-Blake, Annette; Morgan, Ashlea A.; Dumitriu, Dani; Rayport, Stephen; Ansorge, Mark S.

doi:10.1038/s41467-021-27092-z

Cited by 48 publications

(32 citation statements)

References 67 publications

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“…The projection of VTA DA/glutamate neurons to LS has been reported [ 61 , 63 ], but the possible functions of this neural circuit remain unclear. A recent study showed that VTA DA neurons projecting to LS promoted mouse aggression via D2 receptor-mediated inhibition of LS neurons [ 73 ]. Here, we uncover another role of VTA D1 neurons projecting to the LS in relieving anxiety-like behaviors via glutamatergic mechanism.…”

Section: Discussionmentioning

confidence: 99%

D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

Tong

Cui

et al. 2022

Mol Psychiatry

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Dopamine (DA) acts as a key regulator in controlling emotion, and dysfunction of DA signal has been implicated in the pathophysiology of some psychiatric disorders, including anxiety. Ventral tegmental area (VTA) is one of main regions with DA-producing neurons. VTA DAergic projections in mesolimbic brain regions play a crucial role in regulating anxiety-like behaviors, however, the function of DA signal within VTA in regulating emotion remains unclear. Here, we observe that pharmacological activation/inhibition of VTA D1 receptors will alleviate/aggravate mouse anxiety-like behaviors, and knockdown of VTA D1 receptor expression also exerts anxiogenic effect. With fluorescence in situ hybridization and electrophysiological recording, we find that D1 receptors are functionally expressed in VTA neurons. Silencing/activating VTA D1 neurons bidirectionally modulate mouse anxiety-like behaviors. Furthermore, knocking down D1 receptors in VTA DA and glutamate neurons elevates anxiety-like state, but in GABA neurons has the opposite effect. In addition, we identify the glutamatergic projection from VTA D1 neurons to lateral septum is mainly responsible for the anxiolytic effect induced by activating VTA D1 neurons. Thus, our study not only characterizes the functional expression of D1 receptors in VTA neurons, but also uncovers the pivotal role of DA signal within VTA in mediating anxiety-like behaviors.

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Section: Discussionmentioning

confidence: 99%

D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

Tong

Cui

et al. 2022

Mol Psychiatry

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“…In addition, both opioids and psychostimulants have the ability to increase the dopamine level in the NAc [ 30 , 38 ]. Importantly, in animals, an increase in dopamine release in the NAc is associated with increased aggression [ 39 ]. Moreover, substance use can also influence changes in synaptic morphology, including dendritic spine branching and length [ 40 , 41 ], which all contribute to alterations in synaptic activity.…”

Section: Discussionmentioning

confidence: 99%

Effect of Combined Methamphetamine and Oxycodone Use on the Synaptic Proteome in an In Vitro Model of Polysubstance Use

Meyer

Athota

Gowen

et al. 2022

Genes

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Polysubstance use (PSU) generally involves the simultaneous use of an opioid along with a stimulant. In recent years, this problem has escalated into a nationwide epidemic. Understanding the mechanisms and effects underlying the interaction between these drugs is essential for the development of treatments for those suffering from addiction. Currently, the effect of PSU on synapses—critical points of contact between neurons—remains poorly understood. Using an in vitro model of primary neurons, we examined the combined effects of the psychostimulant methamphetamine (METH) and the prescription opioid oxycodone (oxy) on the synaptic proteome using quantitative mass-spectrometry-based proteomics. A further ClueGO analysis and Ingenuity Pathway Analysis (IPA) indicated the dysregulation of several molecular functions, biological processes, and pathways associated with neural plasticity and structural development. We identified one key synaptic protein, Striatin-1, which plays a vital role in many of these processes and functions, to be downregulated following METH+oxy treatment. This downregulation of Striatin-1 was further validated by Western blot. Overall, the present study indicates several damaging effects of the combined use of METH and oxy on neural function and warrants further detailed investigation into mechanisms contributing to synaptic dysfunction.

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“…Vertebrate social behaviors are mainly controlled by two evolutionary conserved and interactive neural circuits ( O’Connell and Hofmann, 2011 ): a “social behavior network” composed of midbrain, hypothalamic, and basal forebrain nuclei that is involved in aggressive, reproductive, and communication behaviors ( Newman, 2017 ); and the reward system corresponding to the mesocorticolimbic dopamine network, that allows social behavior to be reinforcing and, thus, adaptive ( O’Connell and Hofmann, 2011 ). Indeed, recent studies demonstrate that dopamine encodes key aspects of social interactions ( Gunaydin et al, 2014 ), that dopaminergic reward prediction errors guide social learning ( Solié et al, 2021 ), and that dopamine has a role in promoting aggressive behavior in mice ( Golden et al, 2019 ; Mahadevia et al, 2021 ). These findings suggest that the dopaminergic system plays an essential role in social interactions by encoding information about valence (rewarding or aversive social situations), and about social positioning to drive relationship-appropriate behaviors.…”

Section: Dopamine a Neuromodulator At The Interface Between Social Ex...mentioning

confidence: 99%

Social Determinants of Inter-Individual Variability and Vulnerability: The Role of Dopamine

Fauré

Fayad

Prévost-Solié

et al. 2022

Front. Behav. Neurosci.

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Individuals differ in their traits and preferences, which shape their interactions, their prospects for survival and their susceptibility to diseases. These correlations are well documented, yet the neurophysiological mechanisms underlying the emergence of distinct personalities and their relation to vulnerability to diseases are poorly understood. Social ties, in particular, are thought to be major modulators of personality traits and psychiatric vulnerability, yet the majority of neuroscience studies are performed on rodents in socially impoverished conditions. Rodent micro-society paradigms are therefore key experimental paradigms to understand how social life generates diversity by shaping individual traits. Dopamine circuitry is implicated at the interface between social life experiences, the expression of essential traits, and the emergence of pathologies, thus proving a possible mechanism to link these three concepts at a neuromodulatory level. Evaluating inter-individual variability in automated social testing environments shows great promise for improving our understanding of the link between social life, personality, and precision psychiatry – as well as elucidating the underlying neurophysiological mechanisms.

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Dopamine promotes aggression in mice via ventral tegmental area to lateral septum projections

Cited by 48 publications

References 67 publications

D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

Effect of Combined Methamphetamine and Oxycodone Use on the Synaptic Proteome in an In Vitro Model of Polysubstance Use

Social Determinants of Inter-Individual Variability and Vulnerability: The Role of Dopamine

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