Mouse vision as a gateway for understanding how experience shapes neural circuits

Abstract

Genetic programs controlling ontogeny drive many of the essential connectivity patterns within the brain. Yet it is activity, derived from the experience of interacting with the world, that sculpts the precise circuitry of the central nervous system. Such experience-dependent plasticity has been observed throughout the brain but has been most extensively studied in the neocortex. A prime example of this refinement of neural circuitry is found in primary visual cortex (V1), where functional connectivity changes have been observed both during development and in adulthood. The mouse visual system has become a predominant model for investigating the principles that underlie experience-dependent plasticity, given the general conservation of visual neural circuitry across mammals as well as the powerful tools and techniques recently developed for use in rodent. The genetic tractability of mice has permitted the identification of signaling pathways that translate experience-driven activity patterns into changes in circuitry. Further, the accessibility of visual cortex has allowed neural activity to be manipulated with optogenetics and observed with genetically-encoded calcium sensors. Consequently, mouse visual cortex has become one of the dominant platforms to study experience-dependent plasticity.

Keywords: binocularity; development; inhibition; ocular dominance plasticity; visual cortex.

Figure 1

The mouse and human visual systems share basic similarities but differ in complexity. Right, a schematic of the rodent visual system. The eyes in the rodent are positioned laterally resulting in hemi-panoramic vision that includes a narrow central binocular zone (purple) flanked by regions of monocular vison (blue and red). Retinal ganglion cells (RGCs) with receptive fields in the binocular zone from the ipsilateral eye (blue) send a minor projection to a discrete patch in the lateral geniculate nucleus (LGN), whereas the contralateral eye (red) provides the predominant innervation to the LGN. Thalamocortical projections from these two regions converge on the binocular zone (purple) in primary visual cortex (V1). Left, a schematic of the human visual system. Forward facing eyes provide for a more expansive zone of binocular vision. Retinal ganglion cells from the two eyes send similar projections to the LGN that are distributed to eye-specific laminae. Thalamocortical projections similarly converge on V1 (purple) but also maintain evident regions of enrichment termed ocular dominance columns.

Figure 2

Factors governing the expression and duration of OD plasticity operate in numerous subcellular locations. Genes required for OD plasticity (green text) are present both at sites of synaptic contact as well as the somatodendritic compartment. Calcium signaling (Ca2+) through the NMDA receptor (NMDAR) in excitatory pyramidal (PYR) neurons activates several proteins required for OD plasticity including Calmodulin-dependent protein Kinase 2a (CamKII), Protein Kinase A (PKA), Extracellular signal-Regulated Kinase (ERK) and the phosphatase calcineurin. Likewise, Tumor Necrosis Factor alpha (TNFα), Tissue plasminogen activator (TPA) and Brain-Derived Neurotrophic Factor (BDNF) are all required for OD plasticity and may function at excitatory synapses, such as those on dendritic spines (boxed inset). Proteins restricting OD plasticity (red text) to the critical period may also function at synapses, including Nogo Receptor 1 and Lynx1. Calcium-dependent signaling proteins result in the activation of the activity-dependent transcription factor calcium/cyclic AMP binding element (CREB) as well as the immediate early gene activity-regulated cytoskeletal associated protein (ARC). Several extracellular factors are required to close the critical period and inhibit further OD plasticity. These include Chondroitin Sulfate Proteoglycans (CSPGs) that surround Parvalbumin-positive inhibitory neurons and inhibitors associated with myelin membranes. The proper balance of excitatory and inhibitory neurotransmission (E/I balance) is essential both for opening and potentially closing the critical period (orange text). Multiple approaches (not shown) that affect E/I balance affect OD plasticity.