Mazahir T. Hasan Group

A main goal in neuroscience is to understand how information is encoded in neuronal circuits and modified by experience. This goal requires the ability to identify neural correlates of various aspects of animal behavior, from sensory processing to decision-making and motor output. A major challenge is thus the development of methods that would allow 1) measurement of neuronal population activity to identify candidate neural correlates and 2) targeting of the identified cell populations for activity manipulations. An initial critical challenge has been to develop methods that allow measurement of population recordings of neuronal activity with single-cell, single-spike resolution. Population recording of neuronal activity, repeatedly and over long time periods, preferably in freely moving subjects, is therefore a key requirement for studying the dynamic spatio-temporal relationship between neuronal activity, experience-dependent plasticity and behavior.

One possibility for recording neuronal activity at a population level is the robust expression of genes that encode optical reporter molecules such as genetically encoded fluorescent calcium indicator proteins (FCIPs). Our previous work demonstrated for the first time the use of FCIPs in recording neuronal activity in living transgenic mice (Hasan et al., 2004). Subsequently, we recorded activity signals from a large number of neurons with single-spike, single-cell resolution in living animals (Wallace et al., 2008). Recently, we have also succeeded in detecting neuronal activity with a genetic Ca²⁺ sensor in freely moving mice (Lütcke et al., 2010). With these technological advances, it should now be possible to record neuronal activity over months in freely moving mice, and thus study the postnatal maturation of the central nervous system and also observe changes in the activity patterns that occur during learning in mature animals.

We are using the whisker-related somatosensory system of the mouse as a model to study cortical physiology. Each whisker located on the mouse’s snout is anatomically represented in the brain stem, thalamus and cortex as a somatotopic map. Dissecting the role of different cell types in whisker-related information processing in the cortex would help in understanding the role of information coding and learning and memory. Reciprocal interactions between inhibitory and excitatory neurons in thalamocortical and corticocortical pathways are responsible for whisking, object touching and recognition. We plan to target a genetic Ca²⁺ sensor specifically in excitatory and inhibitory neuron types and, simultaneously, record activity dynamics in cortical layer 2/3 neurons to decipher the organization of direction-selective whisker-evoked activity maps.

To understand how different neuron types contribute in columnar information processing, in plasticity and in whisker-related behavior such as object touching and recognition, we plan to reversibly silence excitatory and inhibitory neurons in the somatosensory system, either over very short-time periods (milliseconds) with halorhodopsin or over longer time periods (days and weeks) using tetracycline-controlled expression of tetanus toxin light chain. We plan to achieve our goals by deploying our combinatorial genetic approach that makes use of cell-type-specific tetracycline-transactivator transgenic mice and tetracycline-controlled recombinant adeno-associated viruses for reversible control of gene expression (Zhu et al., 2007).