INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/33855/2/chapter1.pdf · INTRODUCTION The number of people travelling to high altitude regions especially South

INTRODUCTION

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INTRODUCTION

The number of people travelling to high altitude regions especially South America, Nepal and India has risen enormously in the past 10 years. These sojourners (trekkers, tourists and specially troops) as well as people staying at high altitude (HA) such as local residents are exposed to hypobaric hypoxia. Ascent to high altitude leads to decreased partial pressure of oxygen in the atmosphere and results in decrease in alveolar partial pressure of oxygen (Figure 1.1). This reduces oxygen diffusion to the pulmonary artery and causes subsequent reduction in oxygen saturation inside the capillaries. This decreases the oxygen delivery to peripheral tissues which leads to hypobaric hypoxia (HH) (Heath and Williams, 1977). The people who are exposed to HH are commonly confronted with mild problems such as acute mountain sickness (AMS), dizziness, nausea (Bahrke and Hale, 1993), hypophagia (Singh and Selvamurthy, 1993) and motor impairment (Hamilton et al., 1991) or severe problems such as HA pulmonary edema (HAPE) and HA cerebral edema (HACE) (Baily and Davies, 2001; Baumgartner et al., 2002; Chao et al., 1999). Further, many of them experience mental dysfunction and memory deficit (Shukitt Hale et al., 1996). These problems become more severe due to lack of medical care at high altitude.

Figure: 1.1 Tourist, trekkers, troops and local residents at high altitude

HA exposure is considered as an extreme physiological stress inducing wide

range of deleterious effects at cellular level. Recent findings pointed out that exposure to severe hypoxia can cause increased cellular oxidative stress with consequent damage to lipids, proteins and DNA leading to neurodegeneration (Dosek et al., 2007). Earlier, it has been shown that occurrence of oxidative stress in HH (Adcock et


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al., 2000) might play a key role in memory impairment (Maiti et al., 2006). It has deleterious effect on higher brain functions such as memory and cognition (Kramer et al., 1993; Shukitt et al., 1998). Altered neurotransmitter synthesis, elevated level of corticosterone, glutamate excitotoxicity, altered calcium homeostasis and reduced cholinergic transmission have also been implicated in hypoxia induced memory loss (Hota et al., 2008; Barhwal et al., 2009; Muthuraju et al., 2010; Baitharu et al., 2012).

Hypobaric hypoxia is known to cause cognitive dysfunctions owing to the

high oxygen dependency of the brain (Shukitt-Hale et al., 1994). Cognitive and motor deficits have been reported to occur on chronic exposure to HH (Shukitt-Hale et al., 1998). Both acute and chronic exposure to HH results in reduced psychomotor performance, learning abilities, mood disorders and memory impairment (Hornbein et al., 1989; Nicolas et al., 1999; Bolmont et al., 2000; Li et al., 2000). A decline in visual and verbal long term memory is also observed in mountaineers exposed to altitudes ranging from 5488-8848 m for 1-30 days and in volunteers exposed to simulated altitude conditions (Hornbein et al., 1989). Impairment in learning abilities and spatial memory on exposure to altitudes above 5,000 m has also been reported by several workers (Nelson and Gutmann, 1982; Nelson et al., 1990; Cavaletti et al., 1990; Nicolas et al., 1999; Li et al., 2000). The physiological manifestations of HH are however altitude dependent and more pronounced on exposure to very high altitude i.e. 12,000-18,000 ft (3658-5487 m) or extremely high altitude i.e. above 18,000 ft (> 5487 m) (Sukitt-Hale et al., 1996). Magnetic resonance imaging (MRI) studies of high altitude sojourners have shown the occurrence of loss of gray matter and atrophy in several brain regions along with shrinkage in the hippocampus indicating neuronal damage on exposure to high altitude (Sukitt-Hale et al., 1996).

The hippocampus, a region located inside the temporal lobe of the brain, forms

a part of the limbic system and is known to play a key role in explicit memory formation and retrieval. Since the discovery in 1950s by Scoville and Milner that damage to the hippocampal formation causes severe impairment in learning and memory functions in humans, substantial literature has accumulated in an attempt to define its precise role in mammalian behavior (Scoville and Milner, 1957).


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Morphological alterations in the hippocampus have been observed by Hale et al. in HH (Shukitt-Hale et al., 1996). Studies from our laboratory have shown the differential susceptibility of various parts of the brain during exposure to HH; the hippocampal region likely to be more damaged in comparison to cortex and prefrontal cortex (Hota et al., 2007; Maiti et al., 2006). Prolonged exposure to HH induces glutamate excitotoxicity which further mediates calcium induced neurodegeneration (Hota et al., 2008; Barhwal et al., 2009). Additionally, occurrence of glutamate excitotoxicity in the hippocampal region of brain has been reported to be exacerbated by the elevated corticosterone level under the condition of kinate induced oxidative insult and amyloid beta peptide toxicity (Goodman et al., 1996; Roy et al., 2003). Elevated corticosterone level during HH also contributes to hippocampal atrophy and hence memory impairment (Baitharu et al., 2012).

The neuroprotective role of antioxidants like N-acetyl cysteine, Acetyl-L-

Carnitine and BACOPA under HH has been previously demonstrated (Jayalakshmi et al., 2007; Barhwal et al., 2009; Hota et al., 2009) which further validates the occurrence of oxidative stress under HH. Previous reports from our laboratory indicate that induction of glutamate excitotoxicity in hippocampal region on prolonged exposure to HH mediate calcium induced neurodegeneration (Hota et al., 2008; Barhwal et al., 2009). Acetylcholinesterase inhibitors like Physostigmine and Galantamine are found to be neuroprotective against HH (Muthuraju et al., 2009). Additionally, occurrence of glutamate excitotoxicity in the hippocampal region of brain has been reported to be exacerbated by the elevated corticosterone level under hypoxia which can be ameliorated by corticosterone synthesis inhibitor i.e. Metryopone (Baitharu et al., 2012). However supplementation of antioxidants, inhibitors of acetylcholine esterase, NMDA receptor antagonist and removing excess glutamate by Ceftriaxon (B lactum antibiotic through Glutamate transporters) showed limited neuroprotection under hypobaric hypoxic conditions which indicate involvement of other complex mechanism that might trigger survival machinery of neuronal cells (Turner et al., 1985). Moreover many of these inhibitors/antagonists have been found to have side effects and hence there is a necessity to find a modality of ameliorating the hypoxia induced neurodegeneration and memory impairment.


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During last decade, enrichment studies using transgenic mouse models of Huntington’s disease (HD) (Turner et al., 1985) and Alzheimer’s disease (AD) (Faherty et al., 2005) have opened the way for exploring gene-environment interactions in neurodegeneration. Impressive effects of environmental enrichment have also been recently demonstrated in other brain disorders such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), fragile X syndrome, Down syndrome and other neurological disorders (Rampon et al., 2000; Tang et al., 2001; Moser et al., 1997).

Enriched environment (EE) is defined as ‘a combination of complex inanimate

and social stimulation’. Enriched animals are reared in large groups and housed in widely stimulating environments in which a variety of differently shaped objects are present and changed frequently. Various studies have shown that environment enrichment increases dendritic branching and length, the number of dendritic spines and the size of synapses on some neuronal populations (Greenough et al., 1985; Isaac et al., 1992; Connor et al., 1982; Turner and Greenough et al., 1885; Faherty et al., 2005). At the behavioral level, enrichment enhances learning and memory (Rampon 2000; Tang et al., 2001; Moser et al., 1997; Lee et al., 2003), reduces memory decline in aged animals, decreases anxiety and increases exploratory activity (Chapillon et al., 1999; Roy et al., 2000; Friske and Gammie, 2005). The goal of EE is to improve the animals’ quality of life by providing them with a combination of multisensory/cognitive stimulation, increased physical activity, enhanced social interactions and by eliciting natural explorative behaviors. These factors may attribute to underlying mechanism providing neuroprotection against diverse neurological disorders.

Environmental enrichment exerts profound effects on the adult central nervous

system (CNS). A large number of studies highlighted the fact that EE modifies the behavior of animals, leading to a sensitive improvement in complex cognitive functions, particularly learning and memory (Rampon and Tsein, 2000), and positively affecting the animal’s emotional and stress reactivity (Chapillon et al., 2002). Rodents living in EE conditions display increased levels of hippocampal long-


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term potentiation (LTP), a physiological model of synaptic plasticity related to learning and memory (van Praag et al., 2000). This kind of functional improvement is accompanied by prominent changes at the anatomical level, with robust increments in thickness and weight change of cortical region as well as modifications of neuronal morphology in terms of increased dendritic arborization, also in number of dendritic spines, synaptic density and postsynaptic thickening occurring in several regions of the brain particularly in the occipital cortex and hippocampus (Mohammed et al., 2002). Moreover, exposure to EE increases hippocampal neurogenesis and the integration of newly born cells into functional circuits (van Praag et al., 2000). At the molecular level, EE causes a significant change in the expression of a large set of genes involved in neuronal structure, excitability, synaptic transmission and plasticity (Rampon et al., 2000), modulating the synthesis and secretion of neurotrophic factors throughout the brain and affecting the cholinergic, serotoninergic and noradrenergic systems (Rosenweig et al., 1967; Rasmuson et al., 1998; Ickes et al., 2000).

With regard to the cellular and molecular pathways related to neuroprotection,

it has been reported that EE induces members of the neurotrophin family, especially brain-derived neurotrophic factor (BDNF) (Rossi et al., 2005), a possible modulator of neuronal survival and plasticity (Lee and Paffenbarger, 1988). Almli et al. verified that intracerebroventricular BDNF pretreatment resulted in significant protection against hypoxia/ischemia induced morphological damage and spatial memory impairments (Almli et al., 2001). BDNF signaling may eventually converge on the activation of intracellular pathways, leading to the phosphorylation of MAP kinases (e.g. ERK and AKT) which further leads to activation of the transcription factor CREB (Cancedda et al., 2004). Thus, activation of the CREB/CRE transcription pathway may be one crucial mediator of the EE effects on neuronal survival and development. A beneficial effect of housing in an HH on recovery from lesions of the cerebral cortex is a common finding, but it is not known whether enriched-environment can prevent damage from psycho-physiological stress like HH.

It was hypothesized that depletion of neurotrophins may contribute to HH

mediated neurodegeneration and hence memory impairment. Since EE has been


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shown to increase the level of neurotrophins, providing EE during exposure to HH may result in neuroprotection. Despite the availability of literature on beneficial effect of HH on certain neurological disorders, its effects on HH induced memory impairment and neurodegeneration still remains an enigma.

Hence, the present study was undertaken with the following aims and objectives: • To study the effect of enriched environment on hypobaric hypoxia induced

cognitive impairment and neurodegeneration.

• To explore the role of neurotrophins and the mechanism involved in enriched environment mediated neuroprotection during hypobaric hypoxia.


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INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/33855/2/chapter1.pdf · INTRODUCTION The number of people travelling to high altitude regions especially South