Current Research

Pathophysiology and correction of amblyopia, a prevalent form of visual impairment

Amblyopia is a prevalent form of visual disability that arises during infancy and early childhood when inputs to the visual cortex from the two eyes are poorly balanced (for example, by misalignment of the eyes, asymmetric refraction, or opacities and obstructions of one eye). Characteristics of amblyopia are very poor acuity in one eye, and an attendant loss of stereopsis. The need for improved treatments for amblyopia is widely acknowledged.

Animal studies over the past 50 years have uncovered the pathophysiology of amblyopia. It is well documented that temporary monocular deprivation alters the strength of synapses in primary visual cortex that renders cortical neurons unresponsive to stimulation of the deprived eye. Guided by a theory of synaptic modification, we discovered a form of synaptic plasticity—long-term depression (LTD)—that has been shown to be responsible for the rapid loss of visual responsiveness that occurs in visual cortex after monocular deprivation (MD). Numerous manipulations that interfere with the mechanisms of LTD can prevent the effects of MD in visual cortex. However, much less is known about the mechanisms that serve recovery from amblyopia. We recently discovered that temporarily inactivating the retinas sets in motion changes in the brain that enable complete recovery from the effect of early life monocular deprivation when the retinal blockade wears off. Current projects aim to uncover the mechanism for how this recovery of visual function occurs, and to determine if this knowledge can be translated into new and better treatments for amblyopia.

We are investigating the following questions:

  • What is the primary cause of visual impairment after monocular deprivation (MD)?
  • What mechanisms are responsible for changes in the qualities of ocular dominance (OD) plasticity over the lifespan?
  • Can we exploit knowledge of synaptic plasticity and metaplasticity to promote recovery of vision after long-term MD?
  • How does temporary retinal silencing enable recovery from the effects of MD, and is this a viable approach to consider for treatment of human amblyopia?
 

The synaptic substrates of visual recognition memory

Detection of novel stimuli that may predict reward or punishment requires long-term memory for, and recognition of, stimuli that are familiar. Novelty detection and familiarity recognition are often impaired in neuropsychiatric disease, so understanding the neurobiological underpinnings is an important goal. We recently discovered that memory of visual stimulus familiarity is stored via synaptic modifications in primary visual cortex of mice and can be demonstrated using a simple visually-driven reflexive behavior. The primary aims of our research are now to (a) identify how information is stored by the collective activity of neurons in primary visual cortex, (b) pinpoint the key sites in the cortical microcircuit where the essential synaptic modifications occur, and (c) examine a specific hypothesis that memory is expressed by switching the state of activity in the reciprocal connections between visual cortex and thalamus. Also, in collaboration with the laboratory of Dr. Charles Nelson and Boston Children’s Hospital and Harvard Medical School, we are developing a simple assay for use in children based on our observations in mice, with the aim of assessing if it can be used for early detection and stratification of developmental brain disorders. Beyond the relevance of our proposed research to identifying the mechanisms underlying visual recognition memory, they will broaden our understanding of how primary sensory areas are modified by sensory experience in order to modify behavior, which remains one of the great challenges in basic neuroscience.

We are investigating the following questions:

  • How is stimulus-selective response potentiation (SRP) expressed by neurons in V1?
  • In what layers, and in which circuits, are the essential synaptic modifications occurring that support SRP?
  • Is SRP an emergent property of a thalamocortical or cortical-cortical loop?
  • Is SRP and the learned behavioral response to familiar visual stimuli disrupted in mice carrying gene mutations associated with autism and intellectual disability?
 

The pathophysiology and correction of fragile X syndrome and other causes of autism

Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). The main barrier has been identifying the defective cellular processes within the brain that disrupt behavior and cognition. Increasing evidence indicates that many cases of ASD and ID have a genetic etiology. However, these genetic changes are numerous, often very rare, and remarkably diverse. One way to make sense of these findings is to assume that a plethora of gene mutations may similarly disrupt a common set of physiological processes that ultimately manifest behaviorally as ID and ASD. Testing this assumption is of paramount importance, as not only does it narrow the search for mechanisms of disease pathogenesis, but it also suggests therapeutic strategies that might apply broadly to an entire class of etiologies. Work on animal models of single-gene disorders associated with ID and ASD has supported the idea that one axis of pathophysiology is metabotropic glutamate receptor 5 (mGluR5) mediated synaptic protein synthesis and plasticity. In the animal model of fragile X syndrome (FX), mGluR5-mediated protein synthesis and plasticity in the hippocampus are exaggerated and, of particular interest, inhibition of mGluR5 corrects cognitive (and many other) deficits in FX model organisms (flies, mice, and rats). These findings have led to a sea change in the field, showing that disorders once thought to be intractable can be at least partially corrected with appropriate therapy. Although the first attempts to translate these findings into humans with fragile X were not successful, these efforts are continuing. High priorities now are determining why the mGluR5 inhibitors tried to date fell short in clinical trials, and to identify additional therapeutic targets to overcome these limitations.

We are investigating the following questions:

  • What are the molecular mechanisms that couple mGluR5 to protein synthesis, and do these represent novel therapeutic targets for the treatment of fragile X?
  • The effectiveness of mGluR5 inhibitors is often lost with chronic dosing. Why and what can be done to overcome this drug tolerance?
  • What proteins are overexpressed in FX, and how do they contribute to disease phenotypes?
  • How do dendritic spines respond to activation of glutamate receptors and how does this differ in fragile X and wildtype mouse hippocampus?
  • Do other single gene disorders characterized by intellectual disability and autism share the same synaptic pathophysiology as fragile X?