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Aging is a process that presents various alterations in physiological, behavioral and neurochemical processes. It causes impairment of CNS functions which lead to changes in memory, cognition and other behavioral performances. It has been reported that aging causes neurochemical alterations in various physiological functions. The purpose of this study was to assess the cognitive changes in relation to process of aging. For this 20 male rats were taken, 10 young (4-6 months) and 10 old (18-22 months). Morris Water Maze (MWM) was performed to monitor changes in learning and memory while Object-Recognition Test (ORT) was performed to evaluate changes in cognitive function. Results of behavioral tests showed that aged rats had significant impairment of long-term memory. While cognitive ability assessed by ORT was impaired in aged rats. Neurochemical results showed that there was a significant decline in striatum dopamine levels while its metabolite DOPAC was significantly increased in aged rats. Hence aging has a significant negative influence on cognitive functions. Age related behavioral deficits may occur as a result of decline in different neurotransmitter levels in striatum leading to changes in memory and cognitive performance.
Aging is the natural phenomenon, which is the process of growing old and is usually defined as the gradual biological impairment of normal function. These biological changes have direct impact on the functional ability of organs and on the biological systems. These irreversible series of changes inevitably end in death. Physiological senescence of the brain, which includes declining cognition and motor skills, affects the quality of life of many elderly people and represents an important socioeconomic problem (Hedden et al, 2004). Aging causes changes to the brain size, vasculature, and cognition. The brain shrinks with increasing age and there are changes at all levels from molecules to morphology (Peters, 2006).
The aging brain undergoes a myriad of changes resulting in alterations in neuronal functioning and ultimately degeneration of motor and cognitive abilities (Joseph et al, 2009). The most widely acknowledged psychological change with age is the decline in cognitive processes, especially memory (Mather et al, 2005). Cognitive deficits such as learning and memory impairment and delayed amnesia are the debilitating consequences of aging (Balu et al, 2005; Sarkaki et al. 2007). It may include slower thinking, a reduced ability to learn, and impaired memory. Several cognitive functions decline in aging including speed of processing (Salthouse, 1996) and episodic memory (Kuslar, 1994; Backman et al, 2000). Loss of cognitive abilities during aging is a complex process that starts to become evident during middle age in humans (35-65 y old) and rats (12-24 mo old) even in the absence of specific neurodegenerative disease (Kluger et al, 1997). The aged brain exhibits a number of alterations in structure and function, leading to a decline in cognitive and motor abilities (Williams et al, 2009).
Normal aging is associated with a decrease in number and size of neurons, loss of synapses and neuronal branching and with a reduced functioning in neurotransmitter systems, such as the serotonergic and dopamenergic system. These structural and functional alterations have important impact on the behavioural, cognitive and affective status of the individual (Peremans et al; 2002). Dopamine levels decline by around 10% per decade from early adulthood and have been associated with declines in cognitive and motor performance (Peters, 2006; Nyberg et al, 2004; Mukherjee et al, 2002). It has been reported that the dopaminergic pathways between the frontal cortex and the striatum decline with increasing age, or that level of dopamine itself declines, synapses/receptors are reduced or binding to receptors is reduced (Peters, 2006; Nyberg et al, 2004). Serotonin and brain derived neurotrophic factor levels also fall with increasing age and may be implicated in the regulation of synaptic plasticity and neurogenesis in the adult brain (Mattson et al; 2004). Age-related decreases in brain dopamine activity are associated with a decline in cognitive motor function (Volkow et al 1998). Age-related reductions have also been documented for the D1 receptor (Wang et al, 1998) and the dopamine transporter (Van Dyck et al, 1995).
The purpose of present study was to find out the relation between aging and cognitive functions. Previous studies and results have shown a decrease in brain neurotransmitters in advanced age or adulthood. The present study was aimed to investigate the effect of ageing on learning and memory functions in old rats and their relationship with striatum neurotransmitters levels.
Twenty healthy male Albino Wister rats, in two different age groups were purchased from Animal House of HEJ Research Institute of Chemistry, University of Karachi, Pakistan. One group was assigned as “Young (4-6 months)” rats and “Old-age (18-22 months)” rats. The animals were caged separately in plastic cages with free access to tap water and cubes of standard rodent diet during the whole session of experiments. The room temperature was maintained at 22±2°C. Before starting the each experimental session, rats were accustomed to various handling procedures in order to avoid any stress effect. The familiarization was performed in order to nullify the psychological affliction of the environment. All experiments were conducted according to a protocol approved by Local Animal Care Committee.
Twenty male Albino Wistar rats were divided into two groups; Control and Test. Young rats (100-150 grams) were assigned as Control and Old-age rats (300-350 grams) were assigned as Test. After familiarization the following behavioral tests were performed, Water Maze Test and Object-Recognition Test. Rats were then decapitated by Guillotine and brain was removed within 30 seconds from skull after decapitation. The membrane covering the brain was removed with the help of fine forceps. The brain then taken out using spatula was dipped in ice-cold saline. Cerebellum located dorsally covering the brain stem was discarded with forceps. The fresh brain was dipped in ice-cold saline and then placed in brain slicer. In brain slicer striatum region of brain is dissected out. All samples were stored at -70°C until analysis of biogenic amines by HPLC-EC. Frozen striatum samples were homogenized in extraction medium using an electrical homogenizer and neurochemical analysis was performed to estimate DA and DOPAC concentrations in brain. Estimation of DA and its metabolite DOPAC in the rat striatum was done by HPLC-EC method as reported by Haider, et al., 2004. These biogenic amines were detected in a single sample by reversed phase HPLC with electrochemical detector at an operating potential of +0.8. A 5μ Shim-pack ODS separation column of 4.0mm internal diameter and 150mm length was used as the stationary phase. The mobile phase consisting of 0.023% Octyl sodium sulphate (OSS) buffer at pH=2.9 was passed through this column under high pressure by using high pressure pump.
WATER MAZE TEST (WMT):
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The effects on spatial memory were examined by assessing performance in a Water Maze (WM) test designed in our laboratory. Actual Morris Water Maze is circular while we used rectangular maze that has been used before by Plech et al (2000). The method is not same as that described by them. It is a modification of their method. Dimensions of the WM are same as described by them. The WM apparatus used in the present study consisted of a transparent rectangular glass tank (60 x 30cms) filled with room temperature-water, made opaque with powder milk, to the depth of 12cm. A wooden platform (15 x 13cms) was hidden 2cm below the surface of water in a fixed location. Initially the rats were trained and during the training session each rat was placed into the water facing the wall of the tank and allowed 120 seconds to locate and climb onto the submerged platform. The rat was allowed to stay on the platform for 10 seconds. If it failed to find the platform within the allowed time it was guided gently onto the platform. Memory functions of rats were tested by recording the retention latency (RL; the time taken by each rat to locate the hidden platform 24h after training). The cut off time for each session was 2 minutes. 1st trail was for training and 2nd trail was for evaluating short term memory (STM). Interval between trails was important. 2nd trail was performed 60 minutes after training trail. Long term memory (LTM) was measured after 24 hours.
OBJECT RECOGNITION TEST:
The novel object recognition test was introduced by Ennaceur and Delacour in 1988, in order to assess the ability of rats to recognize a novel (new) object in an otherwise familiar environment (Ennaceur & Delacour, 1988). In this test the method performed was described by Okuda in 2007. This test is used to assess memory for interactions with novel objects.The object recognition apparatus consist of square box with the dimensions of 45x45x45cm3. The test is performed in three phases or sessions those are training, familiarization and test session. In the test phase, the time spent exploring the novel object is measured. Non-amnesic animals will spend more time exploring the novel object than the familiar one. An absence of any difference in the exploration of the two objects during the test phase can be interpreted as a memory deficit. To analyze cognitive performance, a discrimination index was calculated as the difference in time exploring the novel and familiar object, expressed as the ratio of the total time spent exploring both objects, which made it possible to adjust for any differences in total exploration time (Okuda et al, 2007).
Results are presented as means ± S.D. Statistical analysis was performed by Student's t-test. Values of p<0.05 were considered as significant.
Fig 3 (a) & (b) show the effect of aging upon short-term memory and long-term memory in young and aged rats. Analysis by t-test showed no effect on short-term memory in aged rats compared to control rats however long-term memory was impaired significantly in old rats as evidenced by an (p<0.01) increase in the latency time. 65 % increase in latency time was exhibited by aged rats compared to controls.
Fig 4 shows the effect of aging upon cognition in rats. Results show a significant (p<0.05) decrease in discrimination index as sniffing time for a new object in aged rats was decreased. A significant (14%) decrease in the discrimination index indicates an impairment of cognition in old rats.
Fig 5 (a) & (b) shows the effect of aging upon striatum Dopamine and DOPAC levels in rats. Analysis by t-test show a significant (p<0.01) decrease in striatum Dopamine levels in aged rats while DOPAC levels in the striatum of aged rats were significantly (p<0.01) increased. Aged rats exhibited a 29% decrease in striatum dopamine levels and 57% increase in striatum DOPAC levels.
Aging is one of the major aspects of human life and has both positive and negative effects on functional abilities of the human being as well as animals. With ageing a number of processes are affected such as memory, learning and other cognitive abilities such as; thought process, abilities to activate and focus attention and so on. Advancing chronological age is associated with impairments in cognition in rodents, as it is in other species. There are numerous reports that aged rats perform worse than young rats on a wide range of learning and memory tests (Barnes, 1990; Kubanis & Zornetzer, 1981; Moscovitch & Winocur, 1992). Much research has focused on understanding the changes in the brain systems that mediate the specific aspects of the observed deficits in aged humans (Albert, 1997; Buckner, 2004) and in animal models of cognitive aging (Gallagher and Rapp, 1997; Wilson et al, 2006). The behavioral assessment of cognitive function in rodent models of ageing provides a basis for understanding biological factors that contribute to these impairments.
In the present study both behavioral and neuropharmacological effects of normal ageing was monitored. The rats of two different age groups young and aged rats were compared and cognitive behavioral parameters such as short-term memory, long-term memory and recognition memory while in the neuropharmacological studies the striatum concentration of Dopamine and its metabolite DOPAC was investigated.
Short-term memory (STM) and long-term memory (LTM) was assessed by water maze test. Our results showed no significant effect of aging on STM while LTM was found to be impaired in older rats. Old rats demonstrated spatial impairment as evidenced by increased latencies to find the hidden platform, as shown by earlier studies (Geng et al, 2007). It is likely that the old rats utilized non-spatial strategies to solve the task, and therefore displayed impairment in learning. However, environmental enrichment has been shown to improve various types of memories in both young and ageing rats (Lauren et al, 2007). Previously oxidative damage was considered as a likely cause of age-associated brain dysfunction because the brain is believed to be particularly vulnerable to oxidative stress due to a relatively high rate of oxygen free radical generation (Forster et al, 1996; Coyle, 1993; Halliwell, 1992; Shoal, 1990; Agarwal et al, 1996). Oxidative damage to mitochondria, protein, and nucleic acid in the brain may also lead to neuronal and cognitive dysfunction. (Lauren et al, 2007). Therefore, the age-related altered behaviors and decrements in memory may be attributed to oxidative damage to the brain.
Cognitive impairment associated with aging was also studied by object recognition test. The results showed a significant decrease in the sniffing time for new object, indicating a cognitive impairment in aged rats. It is consistent with previous studies that 24 hour after training aged rats exhibited impaired recognition memory retention compared to young animals (Maria et al, 2005). It is becoming more and more evident that the effects of age on brain neurotransmitters vary in different brain systems and regions and are often controversial. This study aimed to clarifying the age-related neurotransmitter alterations. To further clarify the relationship the concentrations of DA and its metabolite was simultaneously assayed in striatum. From the neurochemical analysis the results showed that metabolism or turnover of dopamine (DA) was increased but the concentration of DA was decreased in striatum of aged rats. The decrease in DA may be responsible for the observed cognitive deficits.
Aging has a significant effect on both Behavioral and Neurochemical aspects of life. From the present study it is concluded that old-age rats (test rats) show a significant decline in cognitive performance compared to young rats (control rats) and this decline in cognitive performance may be directly related to decreased striatal dopamine levels.