Biomedical subjects

Fernando Gomez-Pinilla

Publications and source records attributed to Fernando Gomez-Pinilla.

15 recordsLinked to original sources

PubMed2006

Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats.

Previous work shows that sleep deprivation impairs hippocampal-dependent learning and long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF), cAMP response-element-binding (CREB) and calcium-calmodulin-dependent protein kinase II (CAMKII) are critical modulators of hippocampal-dependent learning and LTP. In the present study we compared the effects of short- (8 h) and intermediate-term (48 h) sleep deprivation (SD) on the expression of BDNF and its downstream targets, Synapsin I, CREB and CAMKII in the neocortex and the hippocampus. Rats were sleep deprived using an intermittent treadmill system which equated total movement in the SD and control treadmill animals (CT), but permitted sustained periods of rest in CT animals. Animals were divided into SD (treadmill schedule: 3 s on/12 s off) and two treadmill control groups, CT1 (15 min on/60 min off) and CT2 (30 min on/120 min off - permitting more sustained sleep). Real-time Taqman RT-PCR was used to measure changes in mRNA; BDNF protein levels were determined using ELISA. In the hippocampus, 8 h treatments reduced BDNF, Synapsin I, CREB and CAMKII gene expression in both SD and control groups. Following 48 h of experimental procedures, the expression of all these four molecular markers of plasticity was reduced in SD and CT1 groups compared to the CT2 and cage control groups. In the hippocampus, BDNF protein levels after 8 h and 48 h treatments paralleled the changes in mRNA. In neocortex, neither 8 h nor 48 h SD or control treatments had significant effects on BDNF, Synapsin I and CAMKII mRNA levels. Stepwise regression analysis suggested that loss of REM sleep underlies the effects of SD on hippocampal BDNF, Synapsin I and CREB mRNA levels, whereas loss of NREM sleep underlies the effects on CAMKII mRNA.

Animals↗

PubMed2006

Exercise differentially regulates synaptic proteins associated to the function of BDNF.

We explored the capacity of exercise to impact select events comprising synaptic transmission under the direction of brain-derived neurotrophic factor (BDNF), which may be central to the events by which exercise potentiates synaptic function. We used a specific immunoadhesin chimera (TrkB-IgG) that mimics the BDNF receptor, TrkB, to selectively block BDNF in the hippocampus during 3 days of voluntary wheel running. We measured resultant synapsin I, synaptophysin, and syntaxin levels involved in vesicular pool formation, endocytosis, and exocytosis, respectively. Synapsin I is involved in vesicle pool formation and neurotransmitter release, synaptophysin, in the biogenesis of synaptic vesicles and budding, and syntaxin, in vesicle docking and fusion. Exercise preferentially increased synapsin I and synaptophysin levels, without affecting syntaxin. There was a positive correlation between synapsin I and synaptophysin in exercising rats and synapsin I with the amount of exercise. Blocking BDNF abrogated the exercise-induced increases in synapsin I and synatophysin, revealing that exercise regulates select properties of synaptic transmission under the direction of BDNF.

Animals↗

PubMed2006

Revenge of the "sit": how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity.

Exercise, a behavior that is inherently associated with energy metabolism, impacts the molecular systems important for synaptic plasticity and learning and memory. This implies that a close association must exist between these systems to ensure proper neuronal function. This review emphasizes the ability of exercise and other lifestyle implementations that modulate energy metabolism, such as diet, to impact brain function. Mechanisms believed to interface metabolism and cognition seem to play a critical role with the brain derived neurotrophic factor (BDNF) system. Behaviors concerned with activity and metabolism may have developed simultaneously and interdependently during evolution to determine the influence of exercise and diet on cognition. A look into our evolutionary past indicates that our genome remains unchanged from the times of our hunter-gatherer ancestors, whose active lifestyle predominated throughout almost 100% of humankind's existence. Consequently, the sedentary lifestyle and eating behaviors enabled by the comforts of technologic progress may be reaping "revenge" on the health of both our bodies and brains. In the 21st century we are confronted by the ever-increasing incidence of metabolic disorders in both the adult and child population. The ability of exercise and diet to impact systems that promote cell survival and plasticity may be applicable for combating the deleterious effects of disease and ageing on brain health and cognition.

Aging↗

PubMed2006

Neurobiology of exercise.

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

Adaptation, Physiological↗

PubMed2006

Traumatic brain injury induced neuroprotection of retinal ganglion cells to optic nerve crush.

Optic nerve crush injury leads to death of retinal ganglion cells (RGCs), both as a direct result of the primary injury and via secondary degeneration induced by neurotoxins secreted by dying RGCs. Studies have shown that, if optic nerve crush is preceded by an unrelated injury to another part of the central nervous system, for example, the spinal cord, the ensuing T cell-mediated protective autoimmunity results in a significant increase in RGC survival. In this study, we used the controlled cortical impact paradigm to induce unilateral traumatic brain injury (TBI) in rats at different times before they were contralaterally subjected to a mild optic nerve crush. Survival of RGCs, assessed 2 weeks after crush injury, was significantly increased when the crush was inflicted 11 days after TBI, but not when the two injuries were concomitant. The beneficial effect was unaffected by injection of low-dose methylprednisolone MP (1 mg/kg), but was inhibited after a high-dose injection (30 mg/kg). Brain-derived neurotrophic factor (BDNF) mRNA, assayed at intervals after TBI, was increased in the retina ipsilateral to TBI but decreased in the contralateral retina. BDNF peaked 1 day after TBI, decreased on day 11, and rose again on day 21. It thus seems that brain injury sustained a certain time before optic nerve injury has a protective effect on RGC survival. This neuroprotective effect, which appears unrelated to retinal BDNF, is inhibited by high-dose MP, commonly used clinically to treat traumatic optic neuropathy.

Animals↗

PubMed2006

Oxidative stress modulates Sir2alpha in rat hippocampus and cerebral cortex.

Silent information regulator 2 (Sir2) helps survival and longevity in lower organisms during challenging situations. We investigated the possibility that Sir2alpha could be involved with brain plasticity under challenging situations. A diet high in saturated fat and sucrose, which has been shown in rodents to reduce synaptic plasticity and cognition, decreased Sir2alpha levels in the hippocampus and cerebral cortex, in proportion to an increase in protein oxidation. Vitamin E supplementation normalized, in the hippocampus and cerebral cortex, Sir2alpha levels that had been reduced by the high-fat diet. Neither the high-fat diet nor vitamin E supplementation affected cerebellar Sir2alpha. Vitamin E reduced, in the hippocampus, the oxidized nucleic acids that were increased by the high-fat diet. Western blot analysis showed higher contents of Sir2alpha in the hippocampus and cerebellum than in the cerebral cortex. Sir2alpha immunostaining was predominantly localized in the mossy fibre system and the dentate gyrus granule layer of the hippocampal formation. The high-fat diet decreased Sir2alpha immunostaining while vitamin E supplementation reversed these effects. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after high fat consumption and levels were normalized by vitamin E treatment. The present results show that oxidative stress and energy homeostasis associated with the consumption of the high-fat diet are critical for the regulation of Sir2alpha, with important implications for mechanisms of neural repair.

Adenylate Kinase↗

PubMed2006

Exercise affects energy metabolism and neural plasticity-related proteins in the hippocampus as revealed by proteomic analysis.

Studies were conducted to evaluate the effect of a brief voluntary exercise period on the expression pattern and post-translational modification of multiple protein classes in the rat hippocampus using proteomics. An analysis of 80 protein spots of relative high abundance on two-dimensional gels revealed that approximately 90% of the proteins identified were associated with energy metabolism and synaptic plasticity. Exercise up-regulated proteins involved in four aspects of energy metabolism, i.e. glycolysis, ATP synthesis, ATP transduction and glutamate turnover. Specifically, we found increases in fructose-bisphosphate aldolase C, phosphoglycerate kinase 1, mitochondrial ATP synthase, ubiquitous mitochondrial creatine kinase and glutamate dehydrogenase 1. Exercise also up-regulated specific synaptic-plasticity-related proteins, the cytoskeletal protein alpha-internexin and molecular chaperones (chaperonin-containing TCP-1, neuronal protein 22, heat shock 60-kDa protein 1 and heat shock protein 8). Western blot was used to confirm the direction and magnitude of change in ubiquitous mitochondrial creatine kinase, an enzyme essential for transducing mitochondrial-derived ATP to sites of high-energy demand such as the synapse. Protein phosphorylation visualized by Pro-Q Diamond fluorescent staining showed that neurofilament light polypeptide, glial fibrillary acidic protein, heat shock protein 8 and transcriptional activator protein pur-alpha were more intensely phosphorylated with exercise as compared with sedentary control levels. Our results, together with the fact that most of the proteins that we found to be up-regulated have been implicated in cognitive function, support a mechanism by which exercise uses processes of energy metabolism and synaptic plasticity to promote brain health.

Animals↗

PubMed2005

Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition.

The pervasive action of oxidative stress on neuronal function and plasticity after traumatic brain injury (TBI) is becoming increasingly recognized. Here, we evaluated the capacity of the powerful antioxidant curry spice curcumin ingested in the diet to counteract the oxidative damage encountered in the injured brain. In addition, we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain.

Analysis of Variance↗

PubMed2005

License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins.

Exercise has been found to impact molecular systems important for maintaining neural function and plasticity. A characteristic finding for the effects of exercise in the brain and spinal cord has been the up-regulation of brain-derived neurotrophic factor (BDNF). This review focuses on the ability of exercise to impact brain circuitry by promoting neuronal repair and enhance learning and memory by increasing neurotrophic support. A paragon for the role of activity-dependent neurotrophins in the CNS is the capacity of BDNF to facilitate synaptic function and neuronal excitability. The authors discuss the effects of exercise in the intact and injured brain and spinal cord injury and the implementation of exercise preinjury and postinjury. As the CNS displays a capacity for plasticity throughout one's lifespan, exercise may be a powerful lifestyle implementation that could be used to augment synaptic plasticity, promote behavioral rehabilitation, and counteract the deleterious effects of aging.

Aging↗

PubMed2004

The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise.

Following traumatic brain injury (TBI), the brain undergoes a period of metabolic and neurochemical alterations that may compromise the reactivity of neuroplasticity-related molecular systems to physiological stimulation. In order to address the molecular mechanisms underlying plasticity following TBI and the effects of physical stimulation in the acute phase of TBI, levels of intracellular signaling molecules were assessed following voluntary exercise. Lateral fluid percussion injury (FPI) and sham-operated (Sham) rats were housed with or without access to a running wheel (RW) from postsurgery day 0 to 6. Parietal and occipital cortical tissues were analyzed for brain-derived neurotrophic factor (BDNF) using an enzyme-linked immunoabsorbant assay (ELISA). In addition, synapsin I, phospho-synapsin I, cyclic-AMP response-element-binding protein (CREB), phospho-CREB, calcium-calmodulin-dependent protein kinase II (CAMKII), mitogen-activated protein (MAP) kinase I and II (MAPKI and MAPKII), and protein kinase C (PKC) were analyzed by western blot. Results from this study indicated that FPI alone lead to significant increases in synapsin I, CAMKII, and phosphorylated (P) MAPKI (p44) and MAPKII (p42). Exercise in the sham operates led to significant cortical increases of CREB and synapsin I. However, in the FPI rats, the response to exercise was opposite to that seen in the shams in that exercise resulted in significant decreases of CREB, synapsin I, PKC, CAMKII, MAPKI, and MAPKII. Indeed, all the observed proteins in the acutely exercised FPI rats tended to be lower compared to the FPI sedentary (Sed) rats. These results indicate that intracellular signaling proteins are increased during the first week following FPI and that premature voluntary exercise may compromise plasticity.

Animals↗

PubMed2004

Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.

Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal transduction and gene expression, and protect neurons from death. In this study we examined the capacity of dietary omega3 fatty acids supplementation to help the brain to cope with the effects of traumatic injury. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze. This type of lesion also reduced levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB). It is known that BDNF facilitates synaptic transmission and learning ability by modulating synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF and associated synapsin I and CREB, reduced oxidative damage, and counteracted learning disability. The reduction of oxidative stress indicates a benevolent effect of this diet on mechanisms that maintain neuronal function and plasticity. These results imply that omega-3 enriched dietary supplements can provide protection against reduced plasticity and impaired learning ability after traumatic brain injury.

Animals↗

PubMed2004

The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition.

A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF-impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.

We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.

Activating Transcription Factor 1↗

PubMed2002

Alterations in BDNF and synapsin I within the occipital cortex and hippocampus after mild traumatic brain injury in the developing rat: reflections of injury-induced neuroplasticity.

Brain-derived neurotrophic factor (BDNF), its signal transduction receptor trkB, and its downstream effector, synapsin I, were measured in the hippocampus and occipital cortex of young animals after fluid-percussion brain injury (FPI). Isofluorane anaesthetized postnatal day 19 rats were subjected to a mild lateral FPI or sham injury. Rats were sacrificed at 24 h, 7 days, or 14 days after injury in order to determine mRNA expression. Additional animals were sacrificed at 7 and 14 days after injury for protein analysis. Only FPI animals exhibited hemispheric differences in BDNF levels. These animals exhibited a contralateral increase, ranging from 40% to 75%, in BDNF mRNA within both the hippocampus and occipital cortex at 24 h and 7 days after injury. The increase in message within the occipital cortex was accompanied by an increase in BDNF protein at 7 and 14 days after injury. However, hippocampal BDNF protein increased in both hemispheres at postinjury day 7 and was restricted to the ipsilateral hippocampus at postinjury day 14. At postinjury day 7, both trkB and synapsin I mRNA expression increased ipsilaterally and decreased contralaterally in the occipital cortex. In addition, synapsin I phosphorylation was increased by 20% in the ipsilateral cortex and by 30% in the hippocampus on this day. These results indicate that the developing brain responds to a mild injury by modifying factors related to synaptic plasticity and suggest that regions remote from the site of injury express neurotrophic signals potentially needed for compensatory responses.

Animals↗

PubMedDate not supplied

Expression of heat shock protein (HSP)-25 and HSP-32 in the rat spinal cord reconstructed with Neurogel.

We recently showed a successful reconstruction of the cat spinal cord using NeuroGel a polymer hydrogel bridge between the two spinal stumps. The polymer graft supports axonal elongation, myelination and angiogenesis up to 21 months, Wallerian degeneration was diminished and gliotic scarring was prevented. In the present study, we report the expression patterns of two stress proteins, (HSPs) HSP-25 and HSP-32 after spinal cord hemisection with and without reparative surgery with NeuroGel. Double immunofluorescence using cell specific markers for neurons, astrocytes and oligodendrocytes (OL), in combination with antibodies for HSP-25 and 32 showed that mainly neurons express both proteins. Both HSPs displayed different temporal expression patterns in the reconstructed spinal cords with a concomitant reduction of secondary damage. In conclusion, Neurogel reconstruction of the spine during the acute phase considerably reduces secondary damage resulting in a rapid and stable regenerative response.

Animals↗