Evidence in primates supporting the use of chemogenetics for the treatment of human refractory neuropsychiatric disorders

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Chemogenetic manipulation of ventral pallidal neurons impairs acquisition of sign‐tracking in rats

Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward‐paired cue can trigger reward‐seeking behaviours towards the cue itself (i.e. sign‐tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviours, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, the effects of disrupting VP activity in rats on the emergence of sign‐tracking was investigated using chemogenetics, i.e. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Transient disruption of VP neurons [activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N‐oxide (CNO) prior to each autoshaping session] impaired acquisition of sign‐tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e. goal‐tracking) or on the expression of sign‐tracking after it was acquired. In addition, electrophysiological recordings were conducted in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO‐responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. It is argued that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring, compared with expressing, Pavlovian incentive values.     

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal

Background

Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAG^DA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown.

Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission

G protein-coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of G_q and G_i/o GPCR activation on astroglial Ca²⁺-based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while G_qGPCR activation led to cellular activation in both neurons and astrocytes, G_i/oGPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either G_q or G_i/o protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of G_q and G_i/o DREADDs in vivo increased astrocyte Ca²⁺ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia-neuron network operation and brain function.     

Chemogenetic inhibition reveals midline thalamic nuclei and thalamo‐accumbens projections mediate cocaine‐seeking in rats

Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical–basal ganglia‐thalamic circuit. However, our understanding of how this circuit regulates drug‐seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical–basal ganglia‐thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, G_i/o‐coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue‐induced and cocaine‐primed reinstatement of cocaine‐seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue‐induced and cocaine‐primed reinstatement, but had no effect on cue‐induced reinstatement of sucrose‐seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine‐primed reinstatement but enhanced cue‐induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug‐seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse.     

Reverse Pharmacogenetic Modulation of the Nucleus Accumbens Reduces Ethanol Consumption in a Limited Access Paradigm

Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.     

Chemogenetics as a neuromodulatory approach to treating neuropsychiatric diseases and disorders

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Methods for analysis of brain connectivity: An IFCN-sponsored review

The goal of this paper is to examine existing methods to study the “Human Brain Connectome” with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural–functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity.