Nicoletta Berardi

Functional postnatal development of the rat primary visual cortex and the role of visual experience: Dark rearing and monocular deprivation

Postnatal development of rat visual cortical functions was studied by recording extracellularly from the primary visual cortex of 22 animals ranging in age from postnatal day 17 (P17) to P45. We found that in the youngest animals (P17-P19) all visual cortical functions tested were immature. Selectivity for orientation and movement direction of visual stimuli was almost absent, most cells received binocular input and their mean receptive field size was 5-6 times the adult size. Visual acuity was half its adult value. These functional properties developed gradually during the following weeks and by P45 they were all adult-like. This functional development is affected by manipulations of the visual input such as dark rearing (DR) and monocular deprivation (MD). DR prevented the normal postnatal maturation of visual cortical functions: in P60 rats, dark reared from birth, their visual cortical functions resembled those of P19-P21 rats. MD from P15 to P45 resulted in a dramatic shift of the ocular dominance distribution (ODD) in favour of the open eye and in a loss of visual acuity for the deprived eye. To determine the sensitive period of rat visual cortex to MD (critical period) we evaluated the shift in ODD of visual cortical neurones in rats that were subjected to the progressive delay of the onset of fixed MD period (10 days). Our results show that the critical period begins around the end of the third postnatal week, peaks between the fourth and fifth week and starts to decline from the end of the fifth week.

Critical periods during sensory development

Recent studies have made progress in characterizing the determinants of critical periods for experience-dependent plasticity. They highlight the role of neurotrophins, NMDA receptors and GABAergic inhibition. In particular, genetic manipulation of a single molecule, brain-derived neurotrophic factor (BDNF), has been shown to alter the timing of the critical period of plasticity in mouse visual cortex, establishing a causal relation between neurotrophin action, the development of visual function, and the duration of the critical period.

Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice

Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.

Molecular basis of plasticity in the visual cortex.

Sensory experience is known to shape the maturation of cortical circuits during development. A paradigmatic example is the effect of monocular deprivation on ocular dominance of visual cortical neurons. Although visual cortical plasticity has been widely studied since its initial discovery by Hubel and Wiesel >40 years ago, the description of the underlying molecular mechanisms has lagged behind. Several new findings are now beginning to close this gap. Recent data deepen our knowledge of the factors involved in the intercellular communication and intracellular signaling that mediate experience-dependent plasticity in the developing visual cortex. In addition, new findings suggest a role for the extracellular matrix in inhibition of ocular-dominance plasticity in the adult visual cortex.

A re-evaluation of the mechanisms underlying simple cell orientation selectivity

Following from evidence supporting GABA as a putative inhibitory transmitter in the visual cortex, we have iontophoretically applied the GABA antagonist N-methyl bicuculline (Nmb) to simple cells in order to block the inhibitory inputs acting on them. We found that under these conditions previously sharply-tuned simple cells responded equally to all orientations. Moreover receptive field dimensions, judged by the response to stimuli at the optimal and orthogonal orientations, equated best with that expected from a single dLGN cell input. It seems thus, that asymmetries in the excitatory input are not a significant factor in the generation of simple cell orientation selectivity. The asymmetry underlying orientation selectivity rather originates from the operation of an intracortical inhibitory mechanism.

Learning in grating waveform discrimination: Specificity for orientation and spatial frequency

Abstract The effects of practice in the discrimination of briefly flashed gratings were investigated by a forced-choice procedure with error correction in a number of tasks requiring discimination either of pairs of complex gratings of different waveforms or of “simple” (sinusoidal) gratings of slightly different spatial frequency. The percentage of correct responses progressively increases with repetition of trials up to 100–200 trials and then levels off, remaining rather constant thereafter even after days or weeks, in all tasks involving discrimination of complex gratings. However, when the gratings are set perpendicular to those used for the training sessions, or their spatial frequency is changed by 1 octave, the effects of previous perceptual learning are lost, while transfer of learning effects is obtained for smaller changes in orientation (±30°) or spatial frequency (±12 octave). The spatial frequency discrimination of sinusoidal gratings does not improve with a comparable number of trials.

Enrich the environment to empower the brain

Environmental enrichment (EE) has long been exploited to investigate the influence of the environment on brain structure and function. Robust morphological and functional effects elicited by EE at the neuronal level have been reported to be accompanied by improvements in cognitive performance. Recently, EE has been shown to accelerate the development of the visual system and to enhance visual-cortex plasticity in adulthood. These new findings highlight the potential of EE as a promising non-invasive strategy to ameliorate deficits in the maturation of the nervous system and to promote recovery of normal sensory functions in pathological conditions affecting the adult brain.

Reducing Intracortical Inhibition in the Adult Visual Cortex Promotes Ocular Dominance Plasticity

Experience-dependent plasticity in the cortex is often higher during short critical periods in postnatal development. The mechanisms limiting adult cortical plasticity are still unclear. Maturation of intracortical GABAergic inhibition is suggested to be crucial for the closure of the critical period for ocular dominance (OD) plasticity in the visual cortex. We find that reduction of GABAergic transmission in the adult rat visual cortex partially reactivates OD plasticity in response to monocular deprivation (MD). This is accompanied by an enhancement of activity-dependent potentiation of synaptic efficacy but not of activity-dependent depression. We also found a decrease in the expression of chondroitin sulfate proteoglycans in the visual cortex of MD animals with reduced inhibition, after the reactivation of OD plasticity. Thus, intracortical inhibition is a crucial limiting factor for the induction of experience-dependent plasticity in the adult visual cortex.

Acceleration of Visual System Development by Environmental Enrichment

Thus far, the developmental plasticity of the visual system has been studied by altering or reducing visual experience. Here, we investigated whether a complex sensory-motor stimulation, provided by rearing animals in an enriched environment, affects visual system development. We found that raising mice in this condition causes an earlier eye opening, a precocious development of visual acuity, and an accelerated decline of white matter-induced long-term potentiation. These effects are accompanied by a precocious cAMP response element-mediated gene expression and a significant increase of BDNF protein and GAD65/67 expression in enriched pups. In addition, we showed that enriched pups experienced higher levels of licking behavior provided by adult females. Thus, rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development as ascertained at behavioral, electrophysiological, and molecular level.

The cholinergic influence on the function of the cat dorsal lateral geniculate nucleus (dLGN).

The functional influence of the cholinergic input to cat dLGN has been examined by assessing the action of iontophoretically applied acetylcholine (ACh) on the visual responses of cells in layers A and A1. Iontophoretically applied pulses of ACh exerted a strong excitatory action on all 113 cells studied within these layers. In the presence of a sustained application of ACh, the excitatory responses to an optimal stimulus such as a spot of light located within the receptive field centre were greatly facilitated, but at the same time stimulus-specific inhibitory influences were also enhanced. The action of ACh on the stimulus-specific inhibitory influences had the consequence that the responses to non-optimal stimuli were not facilitated to the same extent as those to optimal stimuli and in some cases even diminished. The stimulus-specific inhibitory effects seen in the presence of ACh were very powerful and frequently resulted in complete suppression of the elevated background discharge. We suggest that the ACh directly excites both the relay cells and the Golgi type II inhibitory interneurones within the dLGN. The facilitation of the stimulus-specific inhibition may follow from a direct action on the presynaptic dendrites of the Golgi type II cells which arborize within the dendritic field of the relay cell. Supplementary observations on cells in the perigeniculate nucleus confirm previous findings showing that ACh has an inhibitory effect on these cells. We suggest a tripartite action for the cholinergic influence on the dLGN, involving direct facilitation of relay cells, enhancement of stimulus-specific inhibition via the Golgi type II cells, and disinhibition of the non-specific inhibitory influence form the perigeniculate nucleus.