CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Enriched environment effects on brain development and plasticity

The general aim of this line of research is to investigate the role of the environment in brain development and plasticity, employing the paradigm of Enriched Environment (EE).

In the field of development, in collaboration with L. Maffei, we have shown for the first time that non visual factors can contribute to visual cortical development (Bartoletti et al., 2004). These studies have also shown that retinal development is sensitive to EE (Landi et al., 2007, a e b) and have brought to light a very new role, both at retinal and cortical level, for IGF-1 (Ciucci et al., 2007; Landi et al., 2009). The effects of early exposure to EE might be mediated by the different levels of maternal care received by EE with respect to non EE pups (Sale et al., 2004). We have recently shown that to enrich the environment in terms of body massage promotes brain development, and in particular visual development, in premature infants and in rat pups (Guzzetta et al., 2009), an effect likely mediated by IGF-1.

We are also currently investigating the effects of EE on the development of visual recognition memory in rat pups. The first results indicate that memory for a familiar object is present after a retention interval of 1h but not after a 24 hours retention interval in rat pups at postnatal day 18 (P18) and 25; on the contrary, P18 and P25 EE rat pups show good visual recognition memory both at 1h and 24 h retention interval.

Development of non invasive strategies to promote brain repair

The general aim of this line of research is to develop non invasive strategies to promote brain repair both in animal models of neurodegenerative diseases and of cognitive deficits. The studies in this field, by their contributing to clarify pathogenic mechanisms and to unravel the early presence of alterations in synaptic transmission and plasticity in precisely identified neural circuits, could contribute to design therapeutical strategies to prevent or rescue cognitive deficits and, at the same time, could contribute to our knowledge of the mechanisms crucial for the normal formation of long term memory.

Models of Alzheimer’s disease

It is increasingly evident that cognitive impairments and deficits in synaptic density and synaptic plasticity occur long in advance of the formation of amyloid plaques and of frank neurodegeneration in Alzheimer’s disease (AD) (Jacobsen et al., 2006; Lesnè et al., 2006; Shankar et al., 2008).

The availability of animal models which develop cognitive decline in large advance with respect to AD-like neurodegeneration offers the opportunity to investigate the events that precede and accompany this decline, providing informations essential to understand AD pathogenesis. Amongst the early events, those leading to soluble Beta-amyloid protein (Aß) accumulation and to alterations of synaptic function, density and plasticity are of particular interest. Small, soluble oligomeric forms of amyloid-ß inhibit hippocampal long term potentiation (LTP) and impair cognitive functions. Thus suggests that the early events in AD could include alterations in signal transduction pathways crucial for synaptic plasticity and processes of learning and memory such as ERK, PKA and PKC.

We aim at characterizing the events preceding and accompanying the cognitive decline in animal models of AD, at developing non invasive strategies aimed at preventing or rescuing cognitive deficits and at preventing the onset or reducing the progression of the AD pathology, at characterizing the mechanisms underlying the action of these strategies.

 

We employ the AD11 mouse as a model of NGF deprivation linked progressive neurodegneration which encompasses all hallmarks of human AD (Ruberti et al., 2000; Capsoni et al., 2000) and classical models of familial AD such as the Tg2576. As possible non invasive strategies we are testing the efficacy of Environmental Enrichment (EE) and Intranasal Administration of NGF or BDNF. The results so far obtained show that exposure to EE before cognitive deficits become apparent prevent the onset of memory deficits, rescues the cholinergic deficit and reduces Aß deposition in AD11 mice (Fig. 1); the effects of EE extend beyond the end of enriched housing period (Berardi et al., 2007).

 

A still ongoing study shows that exposure to EE after the cognitive deficits are evident rescues them. Intranasal administration of NGF (De Rosa et al., 2005) or BDNF (experiment in progress)completely rescues visual recognition memory deficits (Fig. 2). These data show the applicative potential of EE in slowing down the progression of the disease in animal models of human neurodegenerative pathologies leading to dementia. As future directions, we shall investigate the events leading to Aß accumulation, the correlation between Aß accumulation in specific brain areas with neural plasticity and cognitive decline, the mechanisms of action underlying EE and NGF/BDNF effects and the effects of isolation on the progression of the disease.

I am currently one of the investigators participating to the “Train the Brain” project coordinated by prof. L. Maffei, aimed at testing the efficacy of interventions based on the “enriched environment” strategy in human subjects with Mild Cognitive Impairment and at investigating their mechanisms of action in animal models.

Models of deficits in memory consolidation

The ERK 1,2 pathway mediates experience-dependent gene transcription in neurons; it has been involved in experience dependent synaptic plasticity and in various forms of long term memory involving hippocampus, amygdala or striatum (Atkins et al., Brambilla et al., 1997; Blum et al., 1999; Mazzucchelli e Brambilla, 2000; Mazzuchelli et al., 2002; Adams and Sweatt, 2002; Schafe et al., 2000; Thomas and Huganir, 2004; Doyere et al., 2007). Visual recognition memory depends on the integrity of structures of the medial temporal lobe. Many evidences indicate that the perirhinal cortex plays an essential role in familiarity-based object recognition (Suzuki et al., 1993; Murray, 1996; Murray and Bussey, 1999; Brown and Aggleton, 2001; Murray, Bussey and Saksida, 2007). It is still unknown whether ERK activation in perirhinal cortex is necessary for visual recognition memory consolidation and whether activation of the ERK pathway affects perirhinal cortex synaptic plasticity. Most important, it is unknown whether by modulating the gain of the ERK pathway it is possible to bidirectionally affect visual recognition memory and perirhinal cortex synaptic plasticity, not only causing an impairment by decreasing the gain but being able to cause an enhancement by increasing it.

 

Our current results indicate that block of ERK activation in the perirhinal cortex impairs consolidation of visual recognition memory. RasGRF1 mice, which exhibit a reduced activation of ERK by neuronal activity (Brambilla et al., 1997; Fasano et al., 2009) have normal short term memory but display a consolidation (Fig. 3) and a reconsolidation deficit. On the contrary, ERK1 ko mice, which have an increased activation of ERK2 in response to glutamate (Mazzucchelli et al., 2002), show a longer lasting visual memory. In parallel with the behavioural data, perirhinal cortex LTD was absent and LTP was significantly smaller in ras GRF1 ko than in wt mice; on the contrary, enhanced LTP and LTD were found in ERK1 ko mice.

Publications

  • Landi S, Ciucci F, Maffei L, Berardi N, Cenni MC (2009) Setting the pace for retinal development: environmental enrichment acts through insulin-like growth factor 1 and brain-derived neurotrophic factor. J. Neurosci. 29:10809-19.
  • 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.
  • Mainardi M, Landi S, Berardi N, Maffei L, Pizzorusso T (2009) Reduced responsiveness to long-term monocular deprivation of parvalbumin neurons assessed by c-Fos staining in rat visual cortex. PLoS ONE 4:e4342.
  • Cunha C, Angelucci A, D'Antoni A, Dobrossy MD, Dunnett SB, Berardi N, Brambilla R (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol. Dis. 33:358-68.
  • 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.
  • Viggiano MP, Giovannelli F, Borgheresi A, Feurra M, Berardi N, Pizzorusso T, Zaccara G, Cincotta M (2008) Disruption of the prefrontal cortex function by rTMS produces a category-specific enhancement of the reaction times during visual object identification. Neuropsychologia 46:2725-31.
  • Corbetta S, D'Adamo P, Gualdoni S, Braschi C, Berardi N, de Curtis I (2008) Hyperactivity and novelty-induced hyperreactivity in mice lacking Rac3. Behav. Brain Res. 186:246-55.
  • Berardi N, Braschi C, Capsoni S, Cattaneo A, Maffei L (2007) Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J. Alzheimers Dis. 11:359-70.
  • Ciucci F, Putignano E, Baroncelli L, Landi S, Berardi N, Maffei L (2007) Insulin-like growth factor 1 (IGF-1) mediates the effects of enriched environment (EE) on visual cortical development. PLoS ONE 2:e475.
  • Pizzorusso T, Berardi N, Maffei L (2007) A richness that cures. Neuron 54:508-10.
  • Landi S, Cenni MC, Maffei L, Berardi N (2007) Environmental enrichment effects on development of retinal ganglion cell dendritic stratification require retinal BDNF. PLoS ONE 2:e346.
  • 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.
  • Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, Fabbri ME, Tessarollo L, Maffei L, Berardi N, Caleo M (2006) Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur. J. Neurosci. 24:1850-6.
  • Pizzorusso T, Medini P, Landi S, Baldini S, Berardi N, Maffei L (2006) Structural and functional recovery from early monocular deprivation in adult rats. Proc. Natl. Acad. Sci. U.S.A. 103:8517-22.
  • De Rosa R, Garcia AA, Braschi C, Capsoni S, Maffei L, Berardi N, Cattaneo A (2005) Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 102:3811-6.
  • Berardi N, Pizzorusso T, Maffei L (2004) Extracellular matrix and visual cortical plasticity: freeing the synapse. Neuron 44:905-8.
  • 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.
  • Bartoletti A, Medini P, Berardi N, Maffei L (2004) Environmental enrichment prevents effects of dark-rearing in the rat visual cortex. Nat. Neurosci. 7:215-6.
  • Berardi N, Pizzorusso T, Ratto GM, Maffei L (2003) Molecular basis of plasticity in the visual cortex. Trends Neurosci. 26:369-78.
  • Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298:1248-51.
  • Di Cristo G, Berardi N, Cancedda L, Pizzorusso T, Putignano E, Ratto GM, Maffei L (2001) Requirement of ERK activation for visual cortical plasticity. Science 292:2337-40.
  • Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A (2000) Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 97:6826-31.
  • Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G, Berardi N, Cattaneo A (2000) Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J. Neurosci. 20:2589-601.
  • Berardi N, Pizzorusso T, Maffei L (2000) Critical periods during sensory development. Curr. Opin. Neurobiol. 10:138-45.

Collaborations

  • Lamberto Maffei
  • Matteo Caleo
  • Maria Cristina Cenni
  • Tommaso Pizzorusso
  • Alessandro Sale
  • Ricardo Brambilla, Università Vita-Salute San Raffaele, Milano.
  • Antonino Cattaneo, Scuola Normale Superiore, Pisa.
  • Giovanni Cioni, Università di Pisa, IRCCS Stella Maris.
  • Massimo Cincotta, ASF, Firenze.
  • Fabio Grohovatz, Fondazione San Raffaele del Monte Tabor, Milano.
  • Maria Pia Viggiano, Università di Firenze.
  • Petra Wahle, Ruhr University, Bochum, Germany.

 

no PI photo

Nicoletta Berardi

Contact information

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Participating staff
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