CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Impact of sensory-motor stimulation and enviromimetics on adult brain plasticity

My main research activity is focused on the influence of environmental stimulation on central nervous system development and plasticity, with particular emphasis on the effects elicited by paradigms of non invasive enriched experience on both the healthy and pathological brain.

Amblyopia recovery in adult rats exposed to environmental enrichment conditions or fluoxetine treatment

Amblyopia, also termed lazy eye, is the most common form of impairment of one eye in adults, with a prevalence of about 3% of the total world population. Amblyopia is caused by early abnormal visual experience owing to anisometropia (unequal refractive power in the two eyes), strabismus (abnormal alignment of one or both eyes) or congenital cataract, resulting in a dramatic loss of visual acuity in an apparently healthy eye and with a great deal of evidence showing that this deficit is also associated with a broad range of other perceptual abnormalities, including deficits in stereopsis and contrast sensitivity. Amblyopia poses a significant and challenging clinical problem because the visual loss is not due to damage within the eye itself but is, rather, due to abnormal processing of visual information in the brain. In animal models, amblyopia can be artificially induced by imposing a long-term reduction of inputs from one eye by lid suture (monocular deprivation). As reported in humans, the classic hallmarks of amblyopia in animal models are a permanent loss of visual acuity in the affected eye and a pronounced ocular dominance shift of visual cortical neurons in favour of the normal eye. Treatment for children involves patching or penalizing the amblyopic eye, and in many cases treatment is unsuccessful, resulting in permanent disability in the form of impaired vision, lack of binocular vision and impaired depth vision. There are currently no treatments available for amblyopic adults. The lack of recovery from amblyopia in the adult is due to a decline of neural plasticity during late postnatal development. Two phases can be indeed defined in the visual cortex, as far as plasticity is concerned: in the first phase, occurring during development of cortical circuits, plasticity is extremely high (critical period), while in the second phase, that characterizes adulthood, plasticity is much lower. During sensory cortex development, neural plasticity allows the maturation of cortical circuits and the development of sensory functions. In the adult, neural plasticity underlies learning processes and is also the basis of the spontaneous attempts of repair after a lesion. An increased plasticity in the adult would strongly favour such attempts, and would considerably enhance the very low degree of recovery that takes place in the mature brain.

Main results

 

I recently performed a study that used a novel approach to treating amblyopia in adulthood (Sale et al., 2007 - Nature Neuroscience). I targeted the abnormal function of the visual cortex in adult amblyopic rats using a non-invasive environmental stimulation based on a so-called Environmental Enrichment setting. Environmental enrichment (EE) is a widely used paradigm to investigate the influence of sensory experience on brain and behaviour. “Enriched” animals are reared in large groups in wide cages where a variety of toys, tunnels and stairs are present and changed frequently. In addition, animals are typically given the opportunity for voluntary physical activity on running wheels. Thus, EE animals have the opportunity for enhanced cognitive interactions, continuous multi-sensorial stimulations provided by the novelty of new objects and high levels of physical activity. We showed that three weeks of EE induce a full recovery of visual acuity and binocularity in adult rats rendered amblyopic by long-term monocular deprivation, i.e. the closure of one eye performed during the critical period and maintained until adulthood. Recovery of plasticity in EE animals was associated with a marked reduction of GABAergic inhibition in the visual cortex, as assessed by brain microdialysis and electrophysiological recordings of synaptic plasticity in visual cortical slices. We also demonstrated that the reduction of inhibition is a crucial molecular mechanism underlying the enhancement of plasticity induced by EE, since restoration of plasticity was completely prevented by benzodiazepine cortical infusion during the EE period. The reduction of cortical inhibition in EE rats is paralleled by an increased expression of the neurotrophin BDNF in the visual cortex contralateral to the recovering (previously amblyopic) eye. Thus, EE is able to reopen the critical period in the adult visual system, reducing levels of non-permissive factors which prevent plasticity in the mature visual cortex (i.e. GABAergic inhibition) and increasing the activity of critical factors able to promote plasticity (i.e. neurotrophins). Investigation of the molecular mechanisms underlying the EE influence on brain plasticity has the promising goal to find possible ‘enviromimetics’, molecules that might be exploited to reproduce the beneficial EE effects. We recently reported that fluoxetine, a drug widely used in clinical psychiatry, completely mimics the enhancement of cortical plasticity elicited by EE, promoting a full recovery of visual functions in adult amblyopic animals (Maya-Vetencourt, Sale et al., 2008 – Science). Moreover, administration of either fluoxetine or BDNF reinstates ocular dominance plasticity after the end of the critical period.

Prospects for the future

 

1. The possibility to induce recovery from amblyopia by using environmental enrichment (EE) is appealing, since it has the potential for application to humans. In order to elaborate novel protocols for amblyopic human subjects it is necessary to characterize the relative contribution given by each of the variables present in the global EE setting to the plasticity enhancement elicited in the adult visual cortex, together with the specific effect of each critical molecular factor set in motion by EE. We are currently exploring the role of visual stimulation, physical exercise, serotonin, BDNF and histone acetylation.

2. Ts65Dn mice are the best characterised transgenic model of Down syndrome, the most common genetic cause of developmental disabilities and mental retardation. It has been recently reported that the cognitive deficits displayed by these mice are associated with alterations in the NGF signal transduction pathway and with excessive hippocampal inhibition, and that they can be rescued by administration of non-competitive antagonists of GABAA receptors. It is unknown, however, whether it is possible to rescue neurotrophic factor signaling or to induce a reduction of GABA-ergic inhibition in Ts65Dn mice through a non-pharmacological approach, which would be of great interest for human subjects with the Down syndrome. My group is investigating the cellular and molecular mechanisms underlying the therapeutic action of environmental enrichment conditions on Ts65Dn mice, with particular emphasis on experience-dependent plasticity processes assessed by a combination of in vivo and in vitro electrophysiology, behavioural analysis and biochemical assays.

3. Age is the major risk factor for dementia. In Italy, there are around 700.000 patients diagnosed with dementia and around 100.000 new cases every year. Among the pathologies which may lead to dementia, Alzheimer's Disease (AD) and vascular dementia (VaD) are by far the most frequent. There are no effective therapeutic strategies for AD or VaD, which are still pathologies orphan of treatment. In the absence of effective pharmacological therapies for dementia, substantial interest has been attracted by methods of cognitive and motor stimulation. Indeed, several anecdotic or correlative studies have demonstrated that the exposure to an “enriched environment” and physical exercise have beneficial effects on brain functioning, specifically in the elderly, and reduce the risk of developing dementia. There are very few studies that rigorously address the effects of the combination of cognitive stimulation and physical exercise in demented patients. Under the scientific coordination of Prof. Lamberto Maffei, we are performing a project aimed at investigating the efficacy of a combination of cognitive training and physical exercise in a homogeneous group of people in the early stages of dementia. In parallel, we are also studying the effects of environmental enrichment on several mouse models of Alzheimer’s disease.

Publications

  • Baroncelli L, Braschi C, Spolidoro M, Begenisic T, Sale A, Maffei L (2010) Nurturing brain plasticity: impact of environmental enrichment. Cell Death Differ. 17:1092-103.
  • Guzzetta A, Baldini S, Bancale A, Baroncelli L, Ciucci F, Ghirri P, Putignano E, Sale A, Viegi A, Berardi N, Boldrini A, Cioni G, Maffei L (2009) Massage accelerates brain development and the maturation of visual function. J. Neurosci. 29:6042-51.
  • Sale A, Berardi N, Maffei L (2009) Enrich the environment to empower the brain. Trends Neurosci. 32:233-9.
  • Spolidoro M, Sale A, Berardi N, Maffei L (2009) Plasticity in the adult brain: lessons from the visual system. Exp Brain Res 192:335-41.
  • Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O'Leary OF, Castrén E, Maffei L (2008) The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320:385-8.
  • Sale A, Cenni MC, Ciucci F, Putignano E, Chierzi S, Maffei L (2007) Maternal enrichment during pregnancy accelerates retinal development of the fetus. PLoS ONE 2:e1160.
  • Sale A, Maya Vetencourt JF, Medini P, Cenni MC, Baroncelli L, De Pasquale R, Maffei L (2007) Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat. Neurosci. 10:679-81.
  • Landi S, Sale A, Berardi N, Viegi A, Maffei L, Cenni MC (2007) Retinal functional development is sensitive to environmental enrichment: a role for BDNF. FASEB J. 21:130-9.
  • Sale A, Putignano E, Cancedda L, Landi S, Cirulli F, Berardi N, Maffei L (2004) Enriched environment and acceleration of visual system development. Neuropharmacology 47:649-60.
  • Cancedda L, Putignano E, Sale A, Viegi A, Berardi N, Maffei L (2004) Acceleration of visual system development by environmental enrichment. J. Neurosci. 24:4840-8.

Grants

2009 to 2012: investigator - Fondazione Cassa di Risparmio di Pisa

2008 to 2009: coordinator - Progetto di Ricerca di Ateneo

2006 to 2007: coordinator - Scuola Normale Superiore

Collaborations

  • Lamberto Maffei
  • Nicoletta Berardi
  • G. Cioni, University of Pisa, Pisa, Italy.
  • G. Bonanno, University of Genoa, Genoa, Italy.
  • P. Luschi, University of Pisa, Pisa, Italy.

 

PI photo

Alessandro Sale

Contact information

email  E-mail

email  +39 050 3153 196

Participating staff
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