Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects

Hare, Brendan D.; Shinohara, Ryota; Liu, Rong Jian; Pothula, Santosh; DiLeone, Ralph J.; Duman, Ronald S.

doi:10.1038/s41467-018-08168-9

Cited by 173 publications

(131 citation statements)

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“…Number 3 March 2020 amygdala, which is necessary and sufficient for the rapid and long-lasting antidepressant actions of ketamine (19,21). Because behavioral tests were conducted 24 hours after dosing to avoid the acute side effects of ketamine, we also acknowledge the possibility that there could be adaptations that require GluN2B on GABA interneurons that mediate the actions of ketamine.…”

Section: Discussionmentioning

confidence: 99%

“…Spontaneous postsynaptic currents were determined before and during bath application of ketamine at 1 μM, the estimated concentration reached in the human brain after i.v. infusion of a dose in the therapeutic range (18) and a concentration that blocks approximately 50% of NMDA-induced currents (19); or 10 μM, a concentration that is sufficient to block approximately 80% of NMDA-induced currents (20). These concentrations have also been used in recent reports (4,13).…”

Section: Gaba Interneurons Are the Cellular Trigger For Ketamine's Ramentioning

confidence: 99%

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GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Gerhard

Pothula

Liu

et al. 2020

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Gaba Interneurons Are the Cellular Trigger For Ketamine's Ramentioning

confidence: 99%

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Gerhard

Pothula

Liu

et al. 2020

Journal of Clinical Investigation

Self Cite

250

169

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“…At the end of the experiment, the enhancement of neuronal activity was further validated by observing increased c-fos expression in mCherry + neurons (Figure 5m). In addition to these results, a recently published study showed that optogenetic activation of Drd1 + mPFC neurons decreases immobility time in the forced swim test, suggesting the possibility that these Drd1-expressing neurons may regulate general aversive or active coping responses 60 . Altogether, our data demonstrate that activating DAsensing mPFC neurons is sufficient to rescue escape behavior after aversive learning.…”

Section: Closed Loop Interactions Between Vta and Mpfc In Aversive Lementioning

confidence: 64%

Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis

Minkowicz

Dumrongprechachan

et al. 2020

Preprint

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Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity in distributed networks, plasticity, and neuromodulatory signaling; yet, the field lacks a unifying framework for its variegated sequelae. Here we build this framework using learned helplessness paradigm, where ketamine restores escape behavior after aversive learning. Lowdimensional optical readout of dopamine (DA) neuron activity across learning predicts acute behavioral responses, transitions through learning phases, and future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of DA signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is regulated by aversive experience and recovered by ketamine in a DA-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising anti-depressant. 3 Ketamine and its S-enantiomer esketamine, which act as antagonists of the glutamatergic N-methyl-Daspartate (NMDA) receptors, demonstrate rapid onset anti-depressant effects in clinical trials 1,2 . Previous studies have shown that ketamine ameliorates depressive-like behaviors in animal models following acute or prolonged stress [3][4][5][6][7] . Accumulating evidence implicates the enhancement of synaptic plasticity in ketamine's behavioral effects 5,6,[8][9][10][11][12] . However, which neural circuit dynamics mediate the effects of this rapidly acting antidepressant on behavior and plasticity are currently unknown.Changes in reward-based and aversive learning represent features of depressive disorders that can be modeled in rodents [13][14][15] . One established model of aversive learning is learned helplessness [16][17][18] . Following prolonged inescapable stress exposure, animals learn that outcomes are independent of their behavioral actions; this learning eventually diminishes attempts to escape from avoidable stressful stimuli 19 . Specific activity patterns of dopaminergic (DA) neurons in the ventral tegmental area (VTA), and downstream DA release, encode reward and aversion [20][21][22][23][24] . This activity is differentially modulated by acute and chronic stress [25][26][27] , regulating depressive-like behaviors [28][29][30] . A recently published meta-analysis suggests that acute sub-anesthetic doses of ketamine may increase DA levels in the cortex, dorsal striatum, and nucleus accumbens 31,32 , but the causal relationship between the DA system and ketamine's effects on neural plasticity and behavior remains to be elucidated. Low dimensional readout of DA neuron activity dynamics in aversive learningTo define the function of midbrain DA neurons during aversive learning, we used a modified model of learned helplessness 5,32 ...

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“…Ketamine’s action on receptors other than the NMDAR, could also contribute to the observed effects. Recent findings indicate that activation of dopamine D1 receptors on pyramidal cells in the prefrontal cortex and/or the action of a metabolite of ketamine on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors might contribute to its long-lasting antidepressant effects (57) (58). However, ketamine’s affinities at other receptors (range of Ki values= 19-131μM) are considerably lower than its affinity for the NMDAR, and it is not clear if ketamine exhibits significant striatal dopamine receptor occupancy in vivo at behaviourally relevant doses (59, 60).…”

Section: Discussionmentioning

confidence: 99%

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

Kokkinou

Irvine

Bonsall

et al. 2019

Preprint

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Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5, P<0.001) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

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Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects

Cited by 173 publications

References 54 publications

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

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