ABSTRACT
The anterior cingulate cortex (ACC) has been implicated in attention deficit hyperactivity disorder (ADHD). More specifically, an appropriate balance of excitatory and inhibitory activity in the ACC may be critical for the control of impulsivity, hyperactivity, and sustained attention which are centrally affected in ADHD. Hence, pharmacological augmentation of parvalbumin- (PV) or somatostatin-positive (Sst) inhibitory ACC interneurons could be a potential treatment strategy. We, therefore, tested whether stimulation of Gq-protein-coupled receptors (GqPCRs) in these interneurons could improve attention or impulsivity assessed with the 5-choice-serial reaction-time task in male mice. When challenging impulse control behaviourally or pharmacologically, activation of the chemogenetic GqPCR hM3Dq in ACC PV-cells caused a selective decrease of active erroneous-i.e. incorrect and premature-responses, indicating improved attentional and impulse control. When challenging attention, in contrast, omissions were increased, albeit without extension of reward latencies or decreases of attentional accuracy. These effects largely resembled those of the ADHD medication atomoxetine. Additionally, they were mostly independent of each other within individual animals. GqPCR activation in ACC PV-cells also reduced hyperactivity. In contrast, if hM3Dq was activated in Sst-interneurons, no improvement of impulse control was observed, and a reduction of incorrect responses was only induced at high agonist levels and accompanied by reduced motivational drive. These results suggest that the activation of GqPCRs expressed specifically in PV-cells of the ACC may be a viable strategy to improve certain aspects of sustained attention, impulsivity and hyperactivity in ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Gyrus Cinguli , Male , Mice , Animals , Parvalbumins , Attention Deficit Disorder with Hyperactivity/drug therapy , Psychomotor Agitation , Impulsive Behavior , InterneuronsABSTRACT
Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.
Subject(s)
GTP-Binding Protein alpha Subunits, Gi-Go/physiology , Gyrus Cinguli/cytology , Gyrus Cinguli/physiology , Pyramidal Cells/physiology , Animals , Clozapine/analogs & derivatives , Clozapine/pharmacology , Female , GTP-Binding Protein alpha Subunits, Gi-Go/drug effects , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression/drug effects , Gyrus Cinguli/drug effects , Humans , Impulsive Behavior/drug effects , Impulsive Behavior/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Pyramidal Cells/cytology , Pyramidal Cells/drug effects , Receptors, Metabotropic Glutamate/drug effects , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/physiology , Signal TransductionABSTRACT
The higher termites (Termitidae) are keystone species and ecosystem engineers. They have exceptional biomass and play important roles in decomposition of dead plant matter, in soil manipulation, and as the primary food for many animals, especially in the tropics. Higher termites are most diverse in rainforests, with estimated origins in the late Eocene (â¼54 Ma), postdating the breakup of Pangaea and Gondwana when most continents became separated. Since termites are poor fliers, their origin and spread across the globe requires alternative explanation. Here, we show that higher termites originated 42-54 Ma in Africa and subsequently underwent at least 24 dispersal events between the continents in two main periods. Using phylogenetic analyses of mitochondrial genomes from 415 species, including all higher termite taxonomic and feeding groups, we inferred 10 dispersal events to South America and Asia 35-23 Ma, coinciding with the sharp decrease in global temperature, sea level, and rainforest cover in the Oligocene. After global temperatures increased, 23-5 Ma, there was only one more dispersal to South America but 11 to Asia and Australia, and one dispersal back to Africa. Most of these dispersal events were transoceanic and might have occurred via floating logs. The spread of higher termites across oceans was helped by the novel ecological opportunities brought about by environmental and ecosystem change, and led termites to become one of the few insect groups with specialized mammal predators. This has parallels with modern invasive species that have been able to thrive in human-impacted ecosystems.
