Amblyopia, which affects 2 to 4% of the human population, exhibits little recovery in adulthood. Prof. Hensch’s discoveries, including the Lynx1-nAChR interaction that restricts adult plasticity, could potentially inspire novel strategies for therapy. Recovery strategies aimed at the Lynx1-nAChR interaction could be fruitful in conjunction with attentional tasks that stimulate cholinergic release (e.g., perceptual learning, video-game training). Clinically approved cholinesterase inhibitors and other small molecules that boost the afferent response and reopen re-wiring of the human visual cortex may therefore be useful for treating amblyopes.

Autism spectrum disorders (ASD) are among the most heritable neurodevelopmental disorders of early childhood with an incidence as high as 1 child in 150. At present, there is no wholly effective treatment. Being able to control the timing of critical periods in different parts of the brain could possibly ameliorate developmental disorders such as autism, in which researchers believe critical periods may be inappropriately accelerated or delayed.

Prof. Hensch’s laboratory is also interested in the transport mechanism that propagates Otx2 from the retina to the cortex. It is possible that Otx2 protein could be used as a carrier for delivering desirable factors or therapeutics to the brain, which could give rise to eye drops for amblyopia or more general systemic treatments for brain disorders such as schizophrenia, in which parvalbumin cells fail to mature properly.

The many types of behavior and perception, like language, hearing and vision, are refined by experiences during critical periods. Retriggering a critical period might also help people learn more readily after childhood and acquire a new language, develop musical abilities or recover from stroke or brain injury.

• Studying how neuronal circuits in the brain are shaped by experiences during 'critical periods' in early postnatal life.
• Investigating the molecular mechanisms of visual and auditory plasticity.
• Exploring reactivation of plasticity in adulthood, which may lead to novel strategies for recovery of function, therapy and lifelong learning.

Popular press about Dr. Hensch's work:

• http://www.scientificamerican.com/article.cfm?id=understanding-the-brains
• http://www.scientificamerican.com/article.cfm?id=adult-lazy-eye-treatments
• http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel454.html
• http://vectorblog.org/2010/12/alzheimer%e2%80%99s-drugs-for-%e2%80%9clazy-eye%e2%80%9d/

• Molecular and genetic tools
• Visual deprivation
• Auditory enrichment
• Mouse imaging
• Electrophysiology
• Brain plasticity assay
• Mouse behavioral assay

Dr. Hensch is also a Professor of Neurology in Children’s Hospital Boston and Harvard Medical School.

Dr Hensch is a Steering Committee member of the Harvard Center on the Developing Child (http://developingchild.harvard.edu/) and on the Faculty of the Harvard Reischauer Insitute of Japanese Studies (http://www.fas.harvard.edu/~rijs/).

Prof. Hensch's research focuses on critical periods in brain development. Critical periods are windows of time in which the brain has a heightened ability to rewire itself in response to input from the environment. Such experience-dependent brain plasticity typically declines after early childhood and the mechanisms that change the brain’s plasticity during onset and closure of the critical periods remain poorly understood. Integrating molecular, cellular and systems neuroscience techniques, and using the developing visual cortex as his model system and the loss of vision, amblyopia, as a clinical readout, Prof. Hensch and his colleagues have successfully identified key inhibitory circuits and proteins that activate the onset and regulate the closure of critical periods.

During an early critical period, monocular occlusion of one eye produces a shift of neuronal response (ocular dominance) in favor of the open eye. Such discordant vision results in an enduring loss of visual acuity, clinically known as amblyopia. Experience-dependent plasticity in the brain requires balanced excitation–inhibition. In one study, the Hensch laboratory has revealed specific, local inhibitory (GABAergic) circuits that trigger a proteolytic (tPA-mediated) reorganization of anatomical connections, which ultimately consolidates plasticity.

The onset of critical periods for vision is delayed in animals that remain in complete darkness from birth. In another study, Prof. Hensch hypothesized that a ‘messenger’ within the visual pathway signals to the developing brain upon the first visual experience, which then triggers the onset of the critical period. The Hensch group has demonstrated that the Otx2 homeoprotein, an essential morphogen for embryonic head formation, is reused later in life as this ‘messenger’ for critical period plasticity. The homeoprotein is stimulated by visual experience to propagate from the retina into the visual cortex, where it is internalized by GABAergic interneurons, especially Parvalbumin-positive cells (PV-cells). Otx2 promotes the maturation of PV-cells, consequently activating critical period onset in the visual cortex. Similarly, other endogenous sources of Otx2 may establish PV-circuitry in other brain regions underlying critical periods for higher cognitive functions.

Amblyopia, which reflects aberrant circuit remodeling within the primary visual cortex exhibits little recovery in adulthood. Therefore, identifying specific biological mechanisms that restrict adult plasticity would inspire potentially novel strategies for therapy. In a recent study, Prof. Hensch hypothesized that the gradual emergence of molecular "brakes" might actively prevent plasticity in the adult brain. By analyzing the transcriptome of the binocular zone in the mouse primary visual cortex for molecules that are expressed more in adulthood than during the critical period, the group has identified a protein, Lynx1, which is an endogenous prototoxin similar to a-bungarotoxin in snake venom and binds to the nicotinic acetylcholine receptor (nAChR). They found that an increase in the expression of Lynx1 protein in mice prevented plasticity in the primary visual cortex late in life. Removal of this molecular brake enhanced nicotinic acetylcholine receptor signaling. Furthermore, they could directly induce visual recovery in adult amblyopic mice by enhancing endogenous acetylcholine signaling. Injection of an acetylcholinesterase inhibitor, physostigmine, restored vision to adult mice initially rendered amblyopic. The results suggest that modulating the balance between excitatory and inhibitory circuits reactivates visual plasticity. These results are now actively being generalized to the auditory system and neurodevelopmental disorders.

Biological Mechanisms and Pathways

• Chondroitin sulphate proteoglycan •
• Electrophysiology •
• GABA •
• Homeoprotein •
• Lynx1-nAChR interaction •
• Molecular biology •
• Nicotinic acetylcholine receptor •
• Otx2 •
• Parvalbumin •
• protease (tissue-type plasminogen activator)
•  

Central Nervous System

• Brain plasticity •
• Critical period •
• Epilepsy •
• Excitatory-inhibitory balance •
• GABA •
• Learning •
• Lynx1-nAChR interaction •
• Nicotinic acetylcholine receptor •
• Nicotinic acetylcholine receptor •
• Plasticity •
• Visual cortex
•  

Disease Mechanisms

• Amblyopia •
• Autism •
• Epilepsy •
• Post-traumatic stress disorder (PTSD) •
• Schizophrenia
•  

Research Tools and Instrumentation

• Auditory enrichment •
• Brain plasticity •
• Genetic engineering •
• Mouse behavior •
• Mouse imaging •
• Visual deprivation
•