Cortical sensory processing is modulated by behavioral and cognitive states. How the modulation is achieved through impacting synaptic circuits remains largely unknown. In awake mouse auditory cortex, we reported that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when animals transitioned from quiescence to active behaviors, while L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings further revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. Changes of behavioral state caused scaling down of excitation and inhibition at an approximately equal level in L2/3 cells, but no synaptic changes in L4 cells. This laminar-specific gain control could be attributed to an enhancement of L1–mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons suppressed as well. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing.

Functional receptive fields of neurons in sensory cortices undergo progressive refinement during development1-4. Such refinement may be attributed to the pruning of non-optimal excitatory inputs, reshaping of the excitatory tuning profile through modifying the strengths of individual inputs, or strengthening of cortical inhibition. These models have not been directly tested, due to the technical difficulties in assaying the spatiotemporal patterns of functional synaptic inputs during development. In this study, in vivo whole-cell voltage-clamp recordings were applied to the recipient layer 4 neurons in the rat primary auditory cortex (A1) to determine the developmental changes in the frequency-intensity tonal receptive fields (TRFs) of their excitatory and inhibitory inputs. To our surprise, co-tuned excitation and inhibition were observed right after the onset of hearing, suggesting that a tripartite thalamocortical circuit with relative strong feedforward inhibition is formed independent of auditory experience. The frequency ranges of tone-driven excitatory and inhibitory inputs first expand within a few days after the hearing onset and then persist into adulthood. The latter phase is accompanied by a sharpening of the excitatory but not inhibitory frequency tuning profile, which results in a relatively broader inhibitory tuning in adult A1 neurons. Thus, the development of cortical synaptic TRFs after hearing onset is marked by a slight breakdown of priorly formed excitation-inhibition balance. Our results suggest that functional refinement of cortical TRFs does not require a selective pruning of inputs, but may depend more on a fine adjustment of excitatory input strengths.

Cortical processing of sensory information initiates from the transformation of thalamically-relayed signals. By optogenetically silencing intracortical circuits to isolate thalamic inputs to layer 4 neurons, we show that intracortical excitation linearly amplifies thalamocortical responses underlying frequency and direction selectivity with preserved spectral range and tuning, and prolongs the response duration. This signal pre-amplification and prolongation enhances the salience of thalamocortically-relayed information and ensures its robust, faithful and more persistent representation.

Formation and retrieval of conditioned fear memories critically depend on the amygdala. Here, we identify an inhibitory projection from somatostatin-positive neurons in the central amygdala to parvalbumin-positive neurons in the zona incerta that is required for both recent and remote fear memories. Thus, amygdala inhibitory input to parvalbumin-positive neurons in the zona incerta, a nucleus not previously implicated in fear memory, is an essential component of the fear-memory circuitry.

Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.