Paola De Bartolo

On whether the environmental enrichment may provide cognitive and brain reserves

The construct of brain and cognitive reserves holds that cognitive enrichment fosters the development of neuroplasticity properties, which permit normal cognitive functioning even in the presence of brain pathology. Interpreting the experience-dependent increase of neuronal connectivity and efficiency in the light of the reserve theory provides an interesting approach for explaining the maintenance of cognitive function observed in some subjects affected by neurodegenerative disorders. In fact, mental and physical engagement with complex environments strengthens synaptic connectivity and provides the means by which preexisting neuronal networks are efficiently utilized and alternative networks are recruited to meet environmental demands and to cope with brain damage. There is considerable interest in determining the biological factors that allow the development of these reserves. To investigate these factors, it is possible to model situations of environmental enrichment in animals that parallel human cognitive enrichment. Experimental findings indicate that early onset and extended housing in an environment with enhanced sensorimotor, cognitive, and social stimulations results in significant changes in brain biochemistry, synaptic connectivity, and neuronal function in enriched animals. These changes provide the groundwork for the improvement of behavioral performance and maintenance of performance following brain damage. As this is the fundamental assumption of the reserve hypothesis, it is possible that as human educational attainment and occupational status, environmental enrichment develops reserves to be spent in the case of a subsequent lesion.

Noise-Induced Hearing Loss (NIHL) as a Target of Oxidative Stress-Mediated Damage: Cochlear and Cortical Responses after an Increase in Antioxidant Defense

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II–III and V–VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18

BackgroundSystemic inflammation might cause neuronal damage and sustain neurodegenerative diseases and behavior impairment, with the participation of pro-inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-18. However, the potential contribution of these cytokines to behavioral impairment in the long-term period has not been fully investigated.MethodsWistar rats were treated with a single intraperitoneal injection of LPS (5 mg/kg) or vehicle. After 7 days and 10 months, the animal behavior was evaluated by testing specific cognitive functions, as mnesic, discriminative, and attentional functions, as well as anxiety levels. Contextually, TNF-α and IL-18 protein levels were measured by ELISA in defined brain regions (that is, frontal cortex, hippocampus, striatum, cerebellum, and hypothalamus).ResultsBehavioral testing demonstrated a specific and persistent cognitive impairment characterized by marked deficits in reacting to environment modifications, possibly linked to reduced motivational or attentional deficits. Concomitantly, LPS induced a TNF-α increase in the hippocampus and frontal cortex (from 7 days onward) and cerebellum (only at 10 months). Interestingly, LPS treatment enhanced IL-18 expression in these same areas only at 10 months after injection.ConclusionsOverall, these results indicate that the chronic neuroinflammatory network elicited by systemic inflammation involves a persistent participation of TNF-α accompanied by a differently regulated contribution of IL-18. This leads to speculation that, though with still unclear mechanisms, both cytokines might take part in long-lasting modifications of brain functions, including behavioral alteration.

Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat.

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. Several studies have investigated functional and anatomical EE effects. However, as EE effects are different according to cerebral region, cortical layer, dendritic field and morphological index considered, a univocal characterization of neuronal morphological changes following rearing in enriched environments is lacking. Aim of the present study was to characterize in the rat the effects of EE on the neuronal morphology of frontal and parietal cortical regions, the main target areas of the stimulation provided by the paradigm. Male Wistar rats were housed in an enriched environment for 3.5 months from the 21st postnatal day. For the morphological analysis, biotinylated dextran amine (BDA)-labeled pyramidal neurons were selected from frontal (M1-M2) and parietal (S1-S2) cortical layers III and V. Apical and basal dendritic branching and spines were analyzed using the Sholl method. Results showed that EE increased branching and spines in both layers of frontal cortex, but had a greater effect on apical arborization. In parietal cortex, EE significantly affected branching and spines in layer III but not layer V neurons, in which only a tendency to be influenced by the rearing conditions was observed in basal arborization. It is hypothesized that these multifaceted morphological EE effects are connected to the heavy involvement of a sensory-motor circuit engaged in the guidance of voluntary action and in motor learning activated by EE stimulation.

Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion

To experimentally verify the reserve hypothesis, the influence of rearing conditions on the cognitive performances and on dendritic spines following basal forebrain lesions was analyzed. Adult rats reared in enriched or standard conditions were depleted of the cholinergic projection to the neocortex by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance in spatial tasks was compared with that of intact animals reared in analogous conditions. Furthermore, number and density of dendritic spines of the layer-III parietal pyramidal neurons were analyzed. Cholinergic depletion of forebrain cortex resulted in impaired performances in most behavioral tasks in animals reared in standard conditions. Conversely, the enriched lesioned animals did not exhibit most deficits evoked by cholinergic lesion, even if some deficits, such as perseverative behaviors, were still present. The pyramidal neurons exhibited an increased spine number and density in the lesioned animals reared in standard conditions. In the enriched lesioned animals, the enhancement of spine number and density elicited by the rearing condition was fully maintained but not further increased in the presence of the lesion. Thus, rearing in an enriched environment results in the development of brain and cognitive reserves that reduce the cognitive impairment following forebrain lesions.

n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations) found in n-3 PUFA supplemented mice also pointed toward an effective neuroprotection. On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

Astrocytic plasticity as a possible mediator of the cognitive improvements after environmental enrichment in aged rats

Currently, little is known about the effect of environmental enrichment (EE) on astrocytic plasticity, especially during aging. Given the newly discovered role of the astrocytes in regulating the synaptic transmission and thereby, the cognitive functions, we aimed to study the impact of EE on the performance in a spatial memory task and on the number and morphology of GFAP immunopositive cells in the dorsal hippocampus. After two months of EE (3 h/per day), the animals were tested in the Radial-Arm Water Maze (RAWM) for four days, with six daily trials. Next, we analyzed the changes in the GFAP immunopositive cells in CA1, CA3 and Dentate Gyrus (DG). Behavioral results showed that, even in advanced ages, EE improved the performance in a spatial memory task. Also, we found that aged rats submitted to EE had more GFAP immunopositive cells in the DG and more complex astrocytes, revealed by Sholl analysis, in all hippocampal subfields with respect to the other experimental conditions. Interestingly, the learning of a spatial memory task produced more morphological complexity and higher levels of GFAP immunopositive cells with regard to a standard control group, but not at the same level of the enriched groups. Thus, it is possible that the plastic changes found in the hippocampal astrocytes after EE are involved in a brain reserve to cope with age-related cognitive impairments.

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimers disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.

Enriched environment improves motor function and increases neurotrophins in hemicerebellar lesioned rats.

Background. Environmental enrichment (EE) defined as “a combination of complex inanimate and social stimulation” influences brain function and anatomy by enhancing sensory, cognitive, motor, and social stimulation. The beneficial effects of EE in the presence of brain damage have been partially attributed to upregulation of neurotrophins, proteins involved in neuronal survival and in activity-dependent plasticity. Objective. The authors tested the hypothesis that EE may have advantageous effects on recovery of motor function after cerebellar damage, associated with changes in local neurotrophin production. Methods. They performed a hemicerebellectomy in rats previously exposed to EE or reared in standard conditions. The time course of compensation of motor symptoms was analyzed in both lesioned groups. Then, the local production of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the spared hemicerebellum and other extracerebellar regions was evaluated. Results. Long-term exposure to EE accelerated the motor recovery in hemicerebellectomized rats and elicited an increase in NGF levels in the spared hemicerebellum, as compared with nonenriched lesioned and control rats. BDNF levels were higher in hemicerebellectomized rats but not influenced by EE. In the frontal cortex, both NGF and BDNF levels were upregulated in hemicerebellectomized enriched rats as compared with hemicerebellectomized nonenriched and control rats. Conclusions. This study suggests that the beneficial effects of EE on motor symptoms after cerebellar damage may be, at least partly, because of modulation of neurotrophic proteins involved in the regeneration processes.

Cognitive performances of cholinergically depleted rats following chronic donepezil administration

Since acute and chronic administration of the acetylcholinesterase inhibitors, namely donepezil, improves cognitive functions in patients afflicted by mild to moderate dementia and reverses memory deficits in experimental models of learning and memory, it seemed interesting to assess the effects of chronic donepezil treatment on cognitive functions in adult rats with forebrain cholinergic depletion. Lesions were performed by means of intracerebroventricular injections of the immunotoxin 192 IgG-saporin. The cognitive functions of lesioned animals treated or not treated with donepezil were compared with those of intact animals. Cholinergic depletion affected working memory functions, weakened procedural competencies, affected the acquisition of localizing knowledge, and evoked remarkable compulsive and perseverative behaviors. In lesioned animals, chronic donepezil treatment ameliorated localizatory capabilities, performances linked to cognitive flexibility and procedural abilities. Furthermore, it attenuated compulsive deficits. The present data indicate positive effects of chronic donepezil treatment on specific cognitive performances, suggesting that an aimed use of acetylcholinesterase inhibitors, targeting some symptoms more than others, may be beneficial in the case of cholinergic hypofunction. The animal model used in the present research may provide an efficient method for analyzing cognition-enhancing drugs before clinical trials.