Chemogenetic Activation of Midbrain Dopamine Neurons Affects Attention, but not Impulsivity, in the Five-Choice Serial Reaction Time Task in Rats

Abstract

Attentional impairments and exaggerated impulsivity are key features of psychiatric disorders, such as attention-deficit/hyperactivity disorder, schizophrenia, and addiction. These deficits in attentional performance and impulsive behaviors have been associated with aberrant dopamine (DA) signaling, but it remains unknown whether these deficits result from enhanced DA neuronal activity in the midbrain. Here, we took a novel approach by testing the impact of chemogenetically activating DA neurons in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) on attention and impulsivity in the five-choice serial reaction time task (5-CSRTT) in rats. We found that activation of DA neurons in both the VTA and SNc impaired attention by increasing trial omissions. In addition, SNc DA neuron activation decreased attentional accuracy. Surprisingly, enhanced DA neuron activity did not affect impulsive action in this task. These results show that enhanced midbrain DA neuronal activity induces deficits in attentional performance, but not impulsivity. Furthermore, DA neurons in the VTA and SNc have different roles in regulating attention. These findings contribute to our understanding of the neural substrates underlying attention deficits and impulsivity, and provide valuable insights to improve treatment of these symptoms.

Chemogenetic Modulation of G Protein‐Coupled Receptor Signalling in Visual Attention Research

“…A noticeable dose‐dependent elevation in omissions was observed at increasing CNO doses for both target regions. Activation of SN also deteriorated discriminative accuracy and mean correct latency, whereas neither activation of SN nor of VTA increased impulsive action, contradictory to their formulated hypothesis . As DREADD expression was only restricted to DA neurons, and not a specific projection, this could have confounded the outcome as the manipulation might be excessive.…”

“…Such tight biological regulation illustrates another strength of DREADD approaches for attentional research purposes, namely the ability to titrate the dosage of DREADD ligands in order to mimic differential catecholamine signalling levels. Therefore, the findings of the Boekhoudt et al [37] study can also suggest that the attentional system is already, before DREADD manipulation, performing close to the normal and optimal state. This means that any intervention either by increasing or decreasing DA neuronal activity will only tip the balance away from optimal performance.…”

“…Therefore, the findings of the Boekhoudt et al . study can also suggest that the attentional system is already, before DREADD manipulation, performing close to the normal and optimal state. This means that any intervention either by increasing or decreasing DA neuronal activity will only tip the balance away from optimal performance.…”

A focus on reward in anorexia nervosa through the lens of the activity‐based anorexia rodent model

“…For example, chemogenetic and optogenetic techniques now allow us to enhance or depress neuronal activity across cellular, circuit‐level or brain‐wide spatial scales and will provide powerful tests of the native, necessary and sufficient causal underpinnings of the physiological and behavioural phenotype of ABA. Studies have already begun using these technologies to show dissociable pathways relevant to AN behaviours, whereby activation of dopamine neurones in the VTA but not the substantia nigra (SN) induced a pronounced and long‐lasting hyperactive phenotype, whereas activation of both VTA and SN dopamine neurones impaired attention in a behavioural assay known as the five choice serial reaction time task . Taking the ABA model into the future by exploiting it in combination with novel neuroscience techniques and technologies will enable us to answer specific questions about the involvement of brain regions and transmitters in behavioural features of ABA.…”

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

“…In the present study, we aimed at further document the in vivo properties of C21 by extending its DREADDs application to transgenic TH-Cre rats. Indeed, TH-Cre rats are frequently used in combination to DREADDs as they appear as a powerful tool for the investigation of tonic modulation of mesolimbic and nigrostriatal dopaminergic (DA) systems in motivated, cognitive and affective behaviors (Beloate et al, 2016;Boekhoudt et al, 2016;Mahler et al, 2014;Runegaard et al, 2019). However, no one has tested yet the potential efficiency and selectivity of C21 in this experimental model.…”