Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Relation of ordinal position signals to the expectation of reward and passage of time in four areas of the macaque frontal cortex

Neurons in several areas of the monkey frontal cortex exhibit rank selectivity, firing differentially as a function of the stage attained during the performance of a serial order task. The activity of these neurons is commonly thought to represent ordinal position within the trial. However, they might also be sensitive to factors correlated with ordinal position including time elapsed during the trial (which is greater for each successive stage) and the degree of anticipation of reward (which probably increases at each successive stage). To compare the influences of these factors, we monitored neuronal activity in the supplementary motor area (SMA), presupplementary motor area (pre-SMA), supplementary eye field (SEF), and dorsolateral prefrontal cortex during the performance of a serial order task (requiring a series of saccades in three specified directions), a variable reward task (in which a cue displayed early in the trial indicated whether the reward received at the end of the trial would be large or small), and a long delay task (in which the monkey had simply to maintain fixation during a period of time approximating the duration of an average trial in the serial order task). We found that rank signals were partially correlated with sensitivity to elapsed time and anticipated reward. The connection to elapsed time was strongest in the pre-SMA. The connection to anticipated reward was most pronounced in the SMA and SEF. However, critically, these factors could not fully explain rank selectivity in any of the areas tested

Differences in the emergent coding properties of cortical and striatal ensembles

The function of a given brain region is often defined by the coding properties of its individual neurons, yet how this information is combined at the ensemble level is an equally important consideration. We recorded multiple neurons from the anterior cingulate cortex (ACC) and the dorsal striatum (DS) simultaneously as rats performed different sequences of the same three actions. Sequence and lever decoding was markedly similar on a per-neuron basis in the two regions. At the ensemble level, sequence-specific representations in the DS appeared synchronously, but transiently, along with the representation of lever location, whereas these two streams of information appeared independently and asynchronously in the ACC. As a result, the ACC achieved superior ensemble decoding accuracy overall. Thus, the manner in which information was combined across neurons in an ensemble determined the functional separation of the ACC and DS on this task