The neural pathways by which information about the acoustic world reaches the auditory cortex are well characterised, but how auditory representations are transformed into motor commands is not known. Here we have used a perceptual decision-making task to study this transformation. We directly demonstrate the role of corticostriatal projection neurones in auditory decisions by specifically manipulating the activity of these neurones in rats performing an auditory frequency discrimination task. Targeted Channelrhodopsin-2 1,2 (ChR2)-mediated stimulation of corticostriatal neurones during the task biased decisions in the direction predicted by the frequency tuning of the stimulated neurones, whereas archaerhodopsin-3 3 (Arch)-mediated inactivation biased decisions in the opposite direction. Striatal projections are widespread in cortex and may provide a general mechanism for the control of motor decisions by sensory cortex.Upon reaching the cortex, auditory information is processed and relayed to a number of cortical and subcortical targets by distinct, largely non-overlapping populations of pyramidal neurones. These targets include parietal cortex, secondary auditory areas, inferior colliculus and striatum, regions which play distinct roles in perception and behaviour. How these outputs help establish associations between sounds and motor responses is unknown.We hypothesized that the projection from the auditory cortex to the striatum carries acoustic information that drives behavioural choices during auditory discrimination. The striatum receives topographic inputs from throughout the cortex. Striatal regions which receive input from motor and prefrontal cortices have been implicated in a wide range of cognitive processes, including decision-making 4 , action selection 5 , and reinforcement learning 6,7 . Through downstream structures of the basal ganglia, the striatum influences the activity in Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Neural circuits are exquisitely organized, consisting of many different neuronal subpopulations. However, it is difficult to assess the functional roles of these subpopulations using conventional extracellular recording techniques because these techniques do not easily distinguish spikes from different neuronal populations. To overcome this limitation, we have developed PINP (Photostimulation-assisted Identification of Neuronal Populations), a method of tagging neuronal populations for identification during in vivo electrophysiological recording. The method is based on expressing the light-activated channel channelrhodopsin-2 (ChR2) to restricted neuronal subpopulations. ChR2-tagged neurons can be detected electrophysiologically in vivo since illumination of these neurons with a brief flash of blue light triggers a short latency reliable action potential. We demonstrate the feasibility of this technique by expressing ChR2 in distinct populations of cortical neurons using two different strategies. First, we labeled a subpopulation of cortical neurons—mainly fast-spiking interneurons—by using adeno-associated virus (AAV) to deliver ChR2 in a transgenic mouse line in which the expression of Cre recombinase was driven by the parvalbumin promoter. Second, we labeled subpopulations of excitatory neurons in the rat auditory cortex with ChR2 based on projection target by using herpes simplex virus 1 (HSV1), which is efficiently taken up by axons and transported retrogradely; we find that this latter population responds to acoustic stimulation differently from unlabeled neurons. Tagging neurons is a novel application of ChR2, used in this case to monitor activity instead of manipulating it. PINP can be readily extended to other populations of genetically identifiable neurons, and will provide a useful method for probing the functional role of different neuronal populations in vivo.

Perceptual decisions are based on the activity of sensory cortical neurons, but how organisms learn to transform this activity into appropriate actions remains unknown. Projections from the auditory cortex to the auditory striatum carry information that drives decisions in an auditory frequency discrimination task1. To assess the role of these projections in learning, we developed a Channelrhodopsin-2-based assay to selectively probe for synaptic plasticity associated with corticostriatal neurons representing different frequencies. Here we report that learning this auditory discrimination preferentially potentiates corticostriatal synapses from neurons representing either high or low frequencies, depending on reward contingencies. We observed frequency-dependent corticostriatal potentiation in vivo over the course of training, and in vitro in striatal brain slices. Our findings suggest a model in which the corticostriatal synapses made by neurons tuned to different features of the sound are selectively potentiated to enable the learned transformation of sound into action.

In the cerebral cortex, the selectivity of neurons for features of sensory stimuli arises through the interaction of excitatory and inhibitory synaptic inputs. Excitatory neurons receive inhibitory input that closely tracks excitation 1-4 , stabilizing network dynamics 5 while improving efficiency and robustness of the neural code 6-8 . However, how this balance of excitation and inhibition is achieved by cortical circuits is unclear, since inhibitory interneurons are thought to pool the inputs of nearby excitatory cells and provide them with non-specific inhibition proportional to the activity of the local network 9-13 . Here we show that although parvalbumin-expressing (PV) inhibitory cells make connections with the majority of nearby pyramidal cells, the strength of their synaptic connections is structured according to the similarity of the cells' responses. Individual PV cells strongly inhibit those pyramidal cells that provide them with strong excitation and share their visual selectivity. This fine-tuning of synaptic weights supports co-tuning of inhibitory and excitatory inputs onto individual pyramidal cells despite dense connectivity between inhibitory and excitatory neurons. Our results indicate that individual PV cells are preferentially integrated into subnetworks of inter-connected, co-tuned pyramidal cells, stabilising their recurrent dynamics. Conversely, weak but dense inhibitory connectivity between subnetworks is sufficient to support competition between them, de-correlating their output. We suggest that the history and structure of correlated firing adjusts the weights of both inhibitory and excitatory connections, supporting stable amplification and selective recruitment of cortical subnetworks.

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel objectrecognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.