Environmental Enrichment Effects in the Cerebellum: History
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Contributor:
Laura Petrosini
,
Francesca Gelfo

The cerebellum is a very plastic brain region that responds to every experience with deep structural and functional rearrangement.

  • environmental enrichment
  • cerebellum
  • cerebellar reserve

1. Introduction

The brain is characterized by the now-recognized capacity of changing its own structure and function in response to stimulations that can come from both internal and external environments, which is known as neuroplasticity [1][2]. Structural and functional plastic rearrangements are triggered by the transmission of information through neuronal circuitries, which react to each experience by circulating electrochemical signals. Such a plastic reorganization occurs during neural system development, when the brain is engaged in learning and memory, and also when the nervous system undergoes damage [3]. In fact, the brain always tends to respond with the maximum possible compensation for damage by reorganizing itself in order to recover as much function as possible and to reach a new homeostatic equilibrium [4][5].
In the context of the studies focused on neuroplasticity, the reserve hypothesis has been formulated. This theory affirms that the experiences that individuals encounter throughout their life affect and fine-tune brain structure and function, providing the individuals with a resilient apparatus [6]. As first observation, it was described that patients affected by Alzheimer’s disease with different life experiences exhibited symptoms in association with different levels of neural injury or degeneration, thus showing different susceptibility to brain damage [7]. This concept has then been enlarged to a wide range of pathological conditions [8]. The concept of reserve evolved over the years; originally articulated in two components—the brain reserve and the cognitive reserve—it is now described as a multifactorial frame. The brain reserve conceptualizes the evidence that an individual that is provided with a more and better structured brain is able to more resiliently face damage. This principle applies to all the components of cerebral structure at molecular and supramolecular levels, such as brain weight and volume, neuron number, neuronal morphology, density and morphology of neuroglia and synapses, structure of circulatory system, neurotransmitters, and neurotrophic factors [9][10][11]. On the other hand, the cognitive reserve is tightly linked to cognitive processes. It can be described as a high-level capacity to efficiently engage the residual functions in order to fulfill tasks and address daily activities [9][10][11]. The neural reserve is intended as a kind of summa of the two previous concepts and regards the ability to efficiently engage neuronal networks and alternative strategies in cognitive performance [9][10][11]. Recently, the concept of brain maintenance has been included in this framework. This idea is somehow similar to the one of brain reserve, and accounts for the capacity of genetics and lifestyle to protect the brain from the development and accumulation of pathological changes [9][10][11]. Finally, it is noteworthy that all these concepts are also linked to the capacity of the brain of compensation, which is the ability of the brain to cope with damage by reacquiring as much function as possible [12].
A fundamental issue on which the studies in this field have focused regards the investigation of the experiential factors that are able to act as “reserve-builders”. Fundamentally, three dimensions are understood to be mainly involved: the cognitive factor, the social factor, and the physical factor [9][10][13]. The cognitive factor regards all the activities that involve the individual by requiring a high-level mental investment. Basically, educational level and job complexity are considered, but a large range of leisure activities may be included in this aspect [14][15][16][17]. The social factor regards the social networks in which the individual is involved. All social relationships fall in this category, in a large range that includes familiar status, parentage, friendship, etc. [18][19]. The physical factor regards the habits that constitute the lifestyle of the individual, such as physical activity, diet, smoking, sleep, alcohol intake, and consumption of beneficial dietary elements [20][21][22].
In animal models, the effects of the enhancement of these three factors on brain structure and function has been studied by using the environmental enrichment (EE) experimental paradigm. The EE paradigm was introduced in the sixties and then widely used with rodents by comparing animals reared in an enriched environment with animals reared in standard laboratory housing conditions [23][24]. By means of this paradigm, it is possible to manipulate the variables concerning rearing conditions with a high-level control. In this way, it is possible to construct a specific design in which to test the effects of a single factor or a combination of factors; to determine the starting, the duration, and the end of the exposure period; to choose the way in which one manipulates each factor (e.g., by stimulating only a sensory channel or more than one in association); and to exactly establish the characteristics of the animals exposed to EE (e.g., species, age, gender, healthy or pathological conditions, etc.) [9][25][26]. Basically, in animals the cognitive factor is mimicked by making the rearing environment more complex, providing the cage with a number of objects of various natures, shapes, sizes, and colors, which are frequently rearranged and replaced, in order to enhance the exposure to novelty; the social factor is mimicked by modulating the number of individuals that are reared in the same cage, typically augmenting the quantity in comparison to the minimum for laboratory standard; the physical factor is mimicked by using cages bigger than the standard ones and equipped with shelves, ladders, and running wheels (frequently indicated as a key-element), to stimulate motor activity and explorative behavior. In addition, specific supplementary diets may be administered [13][26][27][28].
Several studies have used the EE paradigm to model the lifespan experiences of individuals. Consequently, structural and functional cerebral effects of EE have been studied in healthy animals and also in pathological models. In this way, the neuroprotective effects of highly stimulating life experiences have been studied by exposing animals early to a more or less lengthy period of EE before the occurrence of brain damage. Furthermore, the EE paradigm has been used as a versatile paradigm of therapeutic non-pharmacological treatments (useful to enhance spontaneous brain compensation abilities) by exposing animals to a more or less lengthy period of EE after the occurrence of brain damage. On the whole, substantial evidence has been provided by the studies based on the EE paradigm about the experience-empowering impact of EE on the entire brain structure, at both molecular and supramolecular levels [27][29][30][31][32][33][34]. Moreover, motor, behavioral, and cognitive functions have been reported to be improved by the exposure to an enriched environment [26][35][36][37][38]. However, several issues remain open regarding the systematic effects of EE on specific processes and brain regions in relation to the healthy or pathological condition of animals [10][27][29].
A brain region known to greatly respond to somatosensory integration and control with plastic rearrangement, including in adult age, is the cerebellum. This cerebral area is classically known to support high-level cognitive and emotional abilities (such as learning and memory processes, spatial cognition, language, reasoning, emotions, and mood) by recursively rearranging its complex connections with the cortical and sub-cortical regions [39][40][41][42][43][44][45][46][47][48][49][50][51]. Moreover, several studies have documented the cerebellar capacity to compensate deficits derived from damages of multifarious nature [52][53][54][55][56]. Numerous mechanisms at both cellular and sub-cellular levels are involved in such a plastic re-adaptation [4][52][55][57][58][59]. Consequently, it is of great interest to analyze how the environment interacts with the predisposition of the cerebellum to recover functions in the presence of damage. The EE paradigm appears to be an ideal tool for such investigations. Interestingly, Cutuli et al. [60] evaluated the effects of two different EE protocols by exposing animals to an enriched environment only before or only after the ablation of a half of the cerebellum (hemicerebellectomy). By investigating postural and locomotor behaviors, in association with striatal synaptic activity and morphology of interneurons, the reserchers documented that the exposure to EE exerted beneficial effects on the compensation of the cerebellar deficits when the exposure to an enriched environment occurred both before and after the damage.

2. Environmental Enrichment Effects in the Cerebellum of Healthy Animals

Most studies dedicated to cerebellar effects of EE in healthy animals were focused on early exposure, that is, when the rearing of the subjects in an enriched environment started from weaning or even earlier.
Several (n = 10) studies specifically evaluated the effects of an early exposure to EE on synaptic plasticity. De Bartolo et al. [61] reported that a 100-day-long exposure to multidimensional EE—starting from weaning—induced a significant increase in dendritic spine density and size of Purkinje cells both in the vermis and in the hemispheres of adult rats. Such indices of synaptogenesis indicate a substantial strengthening of cerebellar circuitries. Moreover, Kim and colleagues [62] revealed that a 28-day-long exposure to multidimensional EE—starting at 3 weeks of age—induced a selective increase in parallel fiber-to-Purkinje cell synapses of same dendritic origin in mice cerebellum, indicating local synaptic strengthening aimed at the refinement of preexisting cerebellar networks. Conversely, previous studies did not report cerebellar synaptogenesis after early exposure to multidimensional EE. In mice, after a 30-day-long exposure to multidimensional EE from 28 days onwards, Nithianantharajah et al. [63] found unchanged cerebellar levels of synaptophysin, an integral membrane protein in synaptic vesicles. In agreement with this Pascual and Bustamante [64] failed to find changes in rat vermal Purkinje cell dendritic outgrowth after a 10-day-long exposure to multidimensional EE (starting from weaning). The finding of unchanged anxiety-like behavior was associated with such a neural correlate.
The early exposure to EE has also been demonstrated to induce plastic rearrangement in cerebellar molecular factors, such as the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), factors known to be strongly involved in neuronal survival and activity-dependent plasticity. In particular, Angelucci et al. [57] found increased BDNF and NGF expression in the cerebellum of rats exposed to multidimensional EE from weaning for about 120 days. In a more complex investigation, Vazquez-Sanroman et al. [65] analyzed cerebellar BDNF expression in mice exposed to multidimensional EE (but without running wheels, a key element for physical activity enhancement) starting from weaning and lasting for varying periods (1, 4, and 8 weeks). The analysis was performed through immunostaining and immunoblotting, which analyzed the expression of both immature and mature BDNF proteins. After 1 week of exposure, BDNF immunoreactivity was found to be increased only at the granular layer. After 4 and 8 weeks, BDNF immunoreactivity increased at both granular and Purkinje layers. As for the two BDNF protein isoforms, they were both unchanged after 1 week of EE exposure, whereas they were both increased after 8 weeks of EE exposure.
As for neurotransmitter expression, an investigation was conducted by Naka et al. [66] in mice exposed to multidimensional EE for 40 days starting from 28 days of age. They found increased noradrenaline but unchanged serotonin expressions in the cerebellum.
In addition, cerebellar chromatin levels, involved in RNA synthesis, also appear to be influenced by an early exposure to multidimensional EE. Uphouse [67] reported that in rats exposed to multidimensional EE (without running wheels) for 32 days from 28 days of age, cerebellar chromatin levels were increased. However, Uphouse and Tedeschi [68] reported that such change was not present after 60 days of the same treatment.
Finally, Eshra et al. [69] investigated the effects of the exposure of mice to multidimensional EE from birth to 70th–80th postnatal days on cerebellar electrophysiology. Researchers showed a higher granule cell firing frequency induced by EE. This electrophysiological alteration was accompanied by enhanced motor performance.
A few (n = 2) studies investigated the effects on cerebellar structure and function of the exposure of animals to EE occurring later in life. Scholz et al. [70] analyzed the effects of exposing adult mice (7 weeks old) to 24 h or 21 days of multidimensional EE mainly based on a three-level maze, frequently rearranged. The researchers reported a decrease in cerebellar volume, as revealed by in vivo and ex vivo MRI. The volume loss was interpreted to be associated with the synaptic pruning aimed at refining cerebellar circuitry functioning. After the 21-day-long exposure, such a volume change was associated with improved spatial learning. Furthermore, Horvat et al. [71] investigated the effects of a 21-day-long exposure to multidimensional EE (without running wheels) of 6-month-old rats. The researchers reported increased expression of pituitary adenylate cyclase activating polypeptide, which regulates multifarious physiological and pathophysiological processes and exerts neuroprotective action.
Details on the studies cited in this section are provided in Table 1.
Table 1. Studies on environmental enrichment’s effects in healthy animals.
Reference Species
(Age or Weight at the Start of
Environmental Enrichment)		 Environmental Enrichment Type
(Duration)		 Environmental Enrichment Effects on Cerebellar Structure and Function
(Age at the Effect Evaluations)
Uphouse, 1978 [67] Male Fischer rats
(28 days)		 Environmental enrichment
—without running wheels; with novelty manipulation
(32 days)		 Increased chromatin level
(2 months)
Uphouse and Tedeschi, 1979 [68] Male Fischer rats
(28 days)		 Environmental enrichment
—without running wheels; with novelty manipulation
(60 days)		 Unchanged chromatin level
(about 3 months)
Naka et al., 2002 [66] Male ICR mice
(28 days)		 Environmental enrichment
—with running wheels and novelty manipulation
(40 days)		 Increased noradrenaline expression; unchanged serotonin and metabolites expression
(about 2 months)
Nithianantharajah et al., 2004 [63] Female C57BL/6 mice
(28 days)		 Environmental enrichment
—with running wheels and novelty manipulation
(30 days)		 Unchanged synaptophysin level
(about 2 months)
Angelucci et al., 2009 [57] Male Wistar rats
(21 days)		 Environmental enrichment
—with running wheels and novelty manipulation
(about 120 days)		 Increased nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels
(140 days)
Pascual and Bustamante, 2013 [64] Male Sprague–Dawley rats
(22 days)		 Environmental enrichment
—with running wheels and novelty manipulation
(10 days)		 Unchanged anxiety-like behavior
(33–34 days);
unchanged vermal Purkinje cell dendritic outgrowth
(36 days)
Vazquez-Sanroman et al., 2013 [65] Male Balb/c AnNHsd mice
(21 days)		 Environmental enrichment
—without running wheels; with novelty manipulation
(1/4/8 weeks)		 After 1 week: unchanged pro-BDNF and mature BDNF proteins; increased BDNF immunoreactivity at granular layer; unchanged BDNF immunoreactivity at Purkinje layer
(4 weeks)
After 4 weeks: increased BDNF immunoreactivity at granular and Purkinje layers
(7 weeks)
After 8 weeks: increased pro-BDNF and mature BDNF proteins; increased BDNF immunoreactivity at granular and Purkinje layers
(11 weeks)
De Bartolo et al., 2015 [61] Male Wistar rats
(21 days)		 Environmental enrichment
—with running wheels and novelty manipulation
(about 100 days)		 Increased cerebellar Purkinje cell dendritic spine density and size
(about 120 days)
Horvat et al., 2015 [71] Male Wistar rats
(6 months)		 Environmental enrichment
—without running wheels; with novelty manipulation
(21 days)		 Increased pituitary adenylate cyclase activating polypeptide
(PACAP) 27 expression; unchanged PACAP 38 expression
(27 weeks)
Scholz et al., 2015 [70] Male C57BL/B6 mice
(7 weeks)		 Environmental enrichment
—with running wheels and novelty manipulation—based on a three-level maze, without objects
(24 h; 21 days)		 Improved spatial learning
(10 weeks);
decreased volume
(about 7 weeks; 10 weeks)
Eshra et al., 2019 [69] C57BL/6 mice
(at birth)		 Environmental enrichment
—with running wheels and novelty manipulation
(70–80 days)		 Improved motor performance;
higher granule cell firing frequency
(70–80 days)
Kim et al., 2019 [62] C57BL/6 mice
(3 weeks)		 Environmental enrichment
—with running wheels and novelty manipulation
(28 days)		 Selective increase in parallel fiber-to-Purkinje cell synapses of same dendritic origin, with local synaptic strengthening
(7 weeks)
Note: unless otherwise specified, the described effects involve the entire cerebellar structure.

This entry is adapted from the peer-reviewed paper 10.3390/ijerph19095697

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