Assessing neural circuit dynamics of antipsychotic drugs

Treball de fi de grau en Biologia HumanaSupervisora: M. Victòria PuigTutora: Berta AlsinaIn vivo extracellular recording of simultaneous neural responses from different neurons at the same time allows to understand the interaction between neurons and to determine neural dynamics in different brain circuits. These neural responses are transmembrane currents that can be measured in the extracellular space with high temporal resolution (i.e. ms) by placing electrodes extracellularly. Spikes or action potentials are one of the major contributors to the extracellular signal. These are required for effective communication across different brain areas and abnormal spiking activity is found in some neurological diseases. Extracting spikes from extracellular recordings is an arduous task that requires to reliably discern spike contributions from different neurons recorded near the electrode from the background electrical noise. Here, multi-unit activity (i.e. aggregate spiking activity of a neural population close to the electrode) is quantified to assess neural circuit dynamics of antipsychotic drugs in freely-moving mice in the prefronto-hippocampal circuit. Results show that multi-unit activity is reduced by antipsychotic drugs both in hippocampus and medial prefrontal cortex. Decrease in the firing rate of neuronal populations seems to be mediated mainly by the stimulation of serotonin 1A receptor and/or blockage of serotonin 2A receptor

Assessing neural circuit dynamics of antipsychotic drugs

Treball de fi de grau en Biologia HumanaSupervisora: M. Victòria PuigTutora: Berta AlsinaIn vivo extracellular recording of simultaneous neural responses from different neurons at the same time allows to understand the interaction between neurons and to determine neural dynamics in different brain circuits. These neural responses are transmembrane currents that can be measured in the extracellular space with high temporal resolution (i.e. ms) by placing electrodes extracellularly. Spikes or action potentials are one of the major contributors to the extracellular signal. These are required for effective communication across different brain areas and abnormal spiking activity is found in some neurological diseases. Extracting spikes from extracellular recordings is an arduous task that requires to reliably discern spike contributions from different neurons recorded near the electrode from the background electrical noise. Here, multi-unit activity (i.e. aggregate spiking activity of a neural population close to the electrode) is quantified to assess neural circuit dynamics of antipsychotic drugs in freely-moving mice in the prefronto-hippocampal circuit. Results show that multi-unit activity is reduced by antipsychotic drugs both in hippocampus and medial prefrontal cortex. Decrease in the firing rate of neuronal populations seems to be mediated mainly by the stimulation of serotonin 1A receptor and/or blockage of serotonin 2A receptor

Serotonin 5-HT 1A, 5-HT 2A and dopamine D 2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: contribution to the actions of risperidone

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.This work was supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award 23014), SAF2013-49129-C2-2-R and SAF2016-80726-R (AEI / FEDER, UE) by the Spanish Ministry of Economy and Competitiveness (MINECO; to MVP). M.V. Puig is a Ramon y Cajal Investigator (RyC-2012-10042), M. Alemany a FPI predoctoral fellow (BES-2014-070429) from MINECO, and C. Delgado a FI predoctoral fellow (2018FI_B_00112)from the Generalitat de Catalunya (AGAUR