The role of the activity state and the behavioural context

Neocortical networks reveal in vivo spontaneous fluctuating states of neuronal activity, which have been termed UP- and DOWN-states (Luczak et al., 2007;Sachdev et al., 2004;Anderson et al., 2000) (for review Destexhe et al., 2003). The influence of the brain state on membrane potential synchrony has been recently studied in the barrel cortex of behaving mice by two members of the present consortium (Poulet and Petersen, 2008).

            UP- and DOWN-states can be also observed in vitro when the extracellular bathing solution is chosen to more closely mimic the in vivo cerebrospinal fluid milieu (Compte et al., 2003;Shu et al., 2003) or when the modulatory influence of the cholinergic or serotoninergic system is mimicked by application of carbachol and serotonin, respectively (Neubauer and Berger, 2008). The contribution of synaptic activity versus intrinsic activity mediated by voltage-dependent conductances in generating or supporting neocortical UP- or DOWN-states is currently not clear and discussed rather controversial (Waters and Helmchen, 2006). Modifications in intrinsic excitability, synaptic efficacy and local network activity during a cortical UP-state need to be analyzed in more detail and represent one of the goals in the current project grant application. Here, the role of acetylcholine and the cholinergic system, a potent neuromodulatory transmitter system (for review Gu, 2002), will be of central interest in the Research Unit.

            The role of the cholinergic system in cortical processing has been studied in the past (i) by lesioning the cholinergic nuclei in the basal forebrain or by destroying the cholinergic projections, (ii) by electrical stimulation of the cholinergic nuclei, (iii) by local (via iontophoresis) or global application of cholinergic agonists or antagonists, and (iv) by analyzing nicotinic or muscarinic receptor knockout mice. All these approaches have certain advantages, but they will not allow a long-term in vivo analysis of the precise effects of acetylcholine on neocortical processing. Therefore, groups of this Research Unit (SP3 and SP4, Petersen, Poulet) will establish a technique which allows the selective activation of cholinergic neurons using state of the art optical stimulation of genetically targeted neurons (for review Petersen, 2009) (for details see SP4, Poulet and Brecht).