Physiological correlate: ocular dominance plasticity

In their pioneering experiments, Hubel and Wiesel (1962) found that individual neurons in the cat striate cortex respond preferably to visual stimuli that have certain orientation and are within certain visual field. Majority of the cortical neurons were activated by stimulation of either eye; however, some neurons were driven better by one eye stimulation over the other, giving rise to the term “ocular dominance” (OD). Furthermore, they observed that neighboring cells in V1 with similar orientation preference and OD properties are organized in radial columns extending through all layers of the cortex. In young kittens, suturing the contralateral eye led to a dramatic decrease in cortical responsiveness to the deprived eye stimulation (Wiesel and Hubel, 1963b), shifting the OD of neurons towards the open ipsilateral eye already after 3-4 days of deprivation (Hubel and Wiesel, 1970). They also showed that susceptibility to such plastic changes does not extend to the older animals, establishing that there is a critical period for MD-induced ocular dominance plasticity (ODP) (Wiesel and Hubel, 1963b). Detailed understanding of the ODP expression mechanism in juvenile animals came from the chronic single unit recordings in kittens (Mioche and Singer, 1989), where it was shown that, already 6-24h after MD, there is a decreased responsivity to deprived contralateral eye stimulation while open-eye responses remain stable. Later, ODP was also observed in macaque monkeys (Blakemore et al., 1978; Hubel et al., 1977), ferrets (Issa et al., 1999), rats (Rothblat et al., 1978) and finally mice (Dräger, 1978). Thus, the ODP paradigm became a readily available tool to study cortical plasticity in various experimental animals. Availability of variety of genetic tools and the shorter life span of mice has made the mouse visual system an especially attractive model for investigating the molecular and cellular mechanisms of brain plasticity during the critical period and beyond (Espinosa and Stryker, 2012).

Mouse visual system

The basic organization of the mouse visual system is largely similar to other mammals.

the primary visual cortex (V1) through the optic radiation. Whereas fibers from the temporal hemiretina (~20%) do not cross at the optic chiasm and project to the ipsilateral LGN (Dräger and Olsen, 1980) (Fig. 1). Thus, V1 in each cortical hemisphere gets input from both eyes; however, the major input comes from the contralateral eye.

Figure 1. Central visual pathways of a C57Bl/6J mouse [Figure modified from Greifzu et al. (2012)]. Organization of retino-geniculo-cortical visual pathway carrying visual information from the left (green) / right (blue) binocular (darker colors) and monocular (lighter colors) visual fields. Optic nerve fibers carrying information from the nasal hemiretina cross to the contralateral side at the optic chiasm and synapse onto dorsal lateral geniculate neurons (LGN) on the contralateral side, which in turn send axons to the primary visual cortex (V1) through the optic radiation. Fibers from the temporal hemiretina (input from binocular visual field of the eye) do not cross at the optic chiasm and project to the ipsilateral hemisphere (Dräger and Olsen, 1980).

ODP in mice

Mouse V1 lacks cortical orientation and ocular dominance columns seen in cats and macaque monkeys (Hubel and Wiesel, 1962; Hubel et al., 1976). It consists of a monocular area receiving input from only the contralateral eye and binocular area receiving input from both eyes (Dräger, 1975). In the binocular V1, the majority of neurons respond to the contralateral eye stimulation more strongly and thus exhibit contralateral OD (Dräger, 1975). In juvenile mice, binocular V1 undergoes rapid plastic changes after a brief (3-4 day) MD, shifting the OD from contra- to ipsilateral eye (Dräger, 1978), similar to what has been reported in kittens (Mioche and Singer, 1989). Such OD-shifts are mediated by a reduction

in responsivity to the contralateral eye stimulation (Dräger, 1978). The critical period for ODP in mouse is between postnatal days (P)19 to P32 (Gordon and Stryker, 1996). Beyond the critical period for ODP (>P35), 4-d MD does not lead to significant OD-shifts in mice raised in standard-cage conditions (Gordon and Stryker, 1996). Nevertheless, the end of critical period is by no means an abrupt termination of the brain’s plastic potential, as evidenced by experiments wherein a prolonged (7-day) MD could still result in OD-shifts in mice aged up to P110 (Lehmann and Löwel, 2008), and beyond P110 if the MD is further extended (Hosang et al., 2018). Importantly, the mechanism and kinetics of ODP expression is different in juvenile and adult animals. In juvenile-like ODP, 2-3 days after the MD, a reduction in deprived eye responses is observed, which is then followed by an increase in open-eye responses if the MD is prolonged (Frenkel and Bear, 2004). In adult mice, however, a longer (7-d) MD is needed to induce ODP (Lehmann and Löwel, 2008), and the OD-shifts are mediated by an increase in open eye responses (Sato and Stryker, 2008; Sawtell et al., 2003). The studies mentioned above have extensively characterized the ODP in young and adult mice, making it a reliable method of studying the cortical plasticity physiologically (Espinosa and Stryker, 2012).

Moreover, various experimental techniques, such as single unit recordings, visually evoked potentials, two-photon calcium imaging and optical imaging of intrinsic signals, can be utilized to assess the ODP at the single cell or population levels. Among these, optical imaging of intrinsic signals has the advantage of being the least surgically invasive, but lacks cellular resolution (Cang et al., 2005a; Kalatsky and Stryker, 2003). Optical imaging of intrinsic signals is based on the principle that active cortical regions consume more oxygen leading to a local accumulation of deoxyhemoglobin, which in turn absorbs more of the light that is shone onto the surface of skull and can be recorded by a highly sensitive camera after visual stimulation of either eye. Visual cortical maps are then calculated from the acquired frames by performing a Fourier analysis to extract the signal at the stimulation frequency (Cang et al., 2005a; Kalatsky and Stryker, 2003). Pixel intensities of resulting images are assessed to obtain the magnitude of V1 activation after deprived or spared eye

Figure 2: Visualization of neuronal activity using optical imaging of intrinsic signals [Figure modified from Greifzu et al. (2012)]. (A) A white horizontal bar moving upwards or downwards on a black background is presented to an anesthetized mouse. The stimulus activates the neurons in the binocular part of V1. Increased neuronal activity leads to local accumulation of deoxyhemoglobin, which absorbs more of the red light (610 nm) shone onto cortex. Resulting changes in light reflectance are recorded using a light-sensitive CCD camera and are extracted by Fourier analysis. (B) An activity map (top) and retinotopic polar map (bottom) of the binocular zone of V1. The color-coded retinotopic map represents the neuronal response depending on the spatial position of the stimulus in the visual field. Scale bar: 1mm.