Electrophysiological Experimental Tool To Study Synaptic Plasticity Psychology Essay
The impairment in cognitive function due to early life stress has been studied with respect to impairment in Long term potentiation. Bidirectional effects of early life stress on memory and LTP has been reported in various limbic structures based on the stress methods and experimental protocols used. For example, Rearing in limited nesting and bedding material lead to impairment of LTP in hippocampal CA1 areas on high frequency stimulation of Schaffer collaterals, in slice prepared from these rats (Cui et al, 2006). In a similar way, LTP induction in hippocampal dentate gyrus in relation to perforant path stimulation was significantly more under basal conditions in the adult offspring of high licking grooming as compared to offspring of low licking grooming rats (Bagot et al, 2009). This was associated with increased hippocampus dependent learning in contextual fear conditioning test and an increase in spine density in dendrites of DGCs in offspring of High LG mothers. In maternal behaviour studies, low licking grooming behaviour of mother is considered to be associated with stressful events in early life. These behaviours have been shown to influence stress responsiveness and cognitive performance in offspring. In the same study, it was found that administration of corticosterone 100nM or Isoproteronol 1.0 µM lead to a significant increase in LTP induction in low licking grooming offspring. These results suggest that maternal separation leads to adaptive changes in the structure and physiology of areas of brain related to stress, which could be beneficial or harmful depending on the level of threat. In a high threat situation this might be beneficial making the response to be faster while an exaggerated response in a low threat condition might lead to impairment of normal behavioural functions. Another study by (Champagne et al, 2008) showed similar results in hippocampal CA1 cells. This study correlated reduced LTP induction in low LG offspring with low levels of expression of glucocorticoid and mineralocorticoid receptors. At the cellular level these effects could be difficult to explain. The physiological effects of CORT depend on the relative amount of MRs and GRs in the areas of brain like hippocampus, which has expression of both receptors. A balance between occupations of these receptors defines the physiological effects from these areas of brain. MRs are predominantly occupied during basal condition because of their higher affinity for CORT, while GRs are increasingly occupied with higher doses of CORT or chronic stressful conditions. Since levels of these receptors reduce in ELS, during basal conditions, LTP inductions will be expected to be low mainly due to reduced MR dependent reduction in excitation. While during highly stressful conditions or higher doses of CORT administration, a lowering in GRs due to ELS might reduce the inhibitory effect of CORT on LTP.
Handling of rats during early life, which is considered to be a good control for maternal separation stress, is reported to have protective effects due to increased maternal care shown by mothers to the pups. These rats have increased level of GRs and MRs in hippocampus which increases the negative feedback inhibition to HPA axis. Study by (Tang and Zou, 2002) compared the effects of early handling to exposure to novelty induced stress. Exposure to novel environment for 3 minutes daily from PN 1-21 days lead to a significant increase in induction of LTP in CA1 cells of hippocampus, 30 minutes after High frequency stimulation of Schaffer collateral pathways on exposure to novelty in early life. This report is consistent with the reports of ELS inhibiting LTP induction, when the opposite effects of short duration novelty stress to ELS are considered. These results are validated by reports of exposure to brief stress/early handling increasing the level of NR2B subunit expression of NMDA receptors, which might lead to enhancement of LTP (Stamatakis et al, 2009). Neonatally handled rats had higher NR2B subunit mRNA and binding sites in dorsal CA1 hippocampul area along with increased levels in cingulated and somatosensory cortex. Another study by the same group showed that novelty stress enhances the effects of corticosterone on neuronal excitability and plasticity. The inhibitory effect of CORT application on LTP induction in hippocampal slices was enhanced significantly in rats exposed to novelty stress (Zou et al, 2001). Basal level of CORT has predominantly MR dependent effects which also lead to enhancement of LTP induction. While increased level of MRs/GRs in these rats (which leads to enhanced negative feedback to HPA axis) makes them respond more to the inhibitory effect of exogenous CORT, added to the brain slices (Wiegert et al, 2005). Environment enrichment protocol is also reported to be protective against behavioural and cognitive deficits induced by early life stress. Environmental enrichment leads to a significant increase in LTP induction in control rats and reversed the effects of early life stress as well as prenatal stress in young adult rats (Cui et al, 2006; Yang et al, 2007).
Additionally, an in vivo work by (Gruss et al, 2008) studied impact of maternal separation during early life on behavioural stress induced late LTP reinforcement in adulthood. Late LTP is considered as a protein synthesis dependent phase of LTP which lasts for longer periods, more than 8 hours as compared to protein synthesis independent LTP which lasts for around 2 hours. This study showed that 24 hour maternal separation at post natal day 9, lead to an inhibition in late LTP reinforcement by 2 min forced swim test. This effect was not observed in rats which were separated on postnatal day 4 or 18, stressing the importance of stress paradigm during these periods. This study also showed PND 9, which is in stress hyperresponsive period, very critical for the enduring effects of early life stress. (Li et al, 2008) showed effect of sibling deprievation, which is also a potent stressor, on PN 7 also falling in stress-hyper-responsive period to impair performance in Morris Water Maze in female rats.
Furthermore, there are studies in which stress increased LTP induction. For eg., invivo experiments by (Kehoe and Bronzino, 1999; Kehoe et al, 1995) studied impact of early neonatal isolation on dentate gyrus LTP in adult freely moving male and female rats. Rats isolated for 1 hour daily from PND 2-9 from their mother showed enhanced LTP induction as compared to non handled rats. The differences observed in the results observed in LTP induction/inhibition might be attributed to difference in stress protocol used (maternal separation or classification according to licking grooming behaviour) or experimental protocols used (stimulation protocol, the time between stress and LTP induction, whether the experiments are performed on freely moving rats or brain slices) and region of the brains studied. These factors are well discussed in review by (Joels and Krugers, 2007). These differences in the effects of early life stress on LTP induction and inhibition warrants its use directly correlating with memory function.
Most of the studies have focused induction/inhibition of synaptic connections in dentate gyrus or CA1 area of hippocampus with respect to stimulation of perforant path or schaffer collateral respectively. Study from (Blaise et al, 2008) has shown an increase synaptic connections between hippocampal dentate gyrus and baslolateral amygdale on neonatal isolation of rat pups from their mother as well as their siblings 1 hr daily from postnatal day 2-9. Basolateral amygdale mediates emotional and fear responses to stress as well as effects formation of hippocampal dependent memory formation. Increased LTP between these regions could have important implications for stress induced emotional memory. This study could also explain an increased synaptic excitability in rats exposed to early life stress during pathological conditions like epilepsy (Salzberg et al, 2007). Early life stress protocols like maternal separation lead to increased rate of progression of kindling stimulations to reach stage V of seizures according to classification described by (Racine et al, 1972). Similarities in the pathways of kindling and long term potentiation are discussed in review by (McEachern and Shaw, 1996). Prior induction of LTP in the pathway from enterorhinal cortex and dentate gyrus decreased subsequent number of stimulations needed to reach fully kindled state (Sutula and Steward, 1987). The opposite was also true as there was an increase in the induction of LTP after a single kindling stimulus that evoked after discharge but had minimal behavioural seizures (Sutula and Steward, 1986). These facts are also supported by reports of low frequency stimulations similar to those which induce long term depression in deep brain regions immediately after kindling stimulations, delayed the epileptogenesis process in amygdaloid kindling seizures (Velisek et al, 2002; Wang et al, 2008; Wu et al, 2008). Interestingly, low frequency stimulations given once daily for a week (without concurrent kindling stimulations), in fully kindled rats inhibited seizure development when stimulations were commenced (Weiss et al, 1995). (Pavlides et al, 2002) showed that choronic stress during adulthood leads to inhibition in the development of LTP in both CA1 and dentate granule cells, which is consistent with the reports of effect of early life stress. But high frequency stimulations which were used for development of LTP evoked epileptic discharges in 56% of acutely stressed rats, 29% of chronically stressed rats while 9% only in non stressed rats. This is contrary to the expectation that LTP and kindling seizures progress in same direction. Moreover, early life stress leads to suppression of LTP and cognitive functions while it leads to increased rate of epileptogenesis process (Salzberg et al, 2007). Also, despite many reported similarities in molecular pathways between LTP and kindling process, differences in the molecular pathways have also been reported (Heida et al, 2009). Protein kinase M zeta which is important for the development of LTP and memory formation has not been implicated in progression of limbic seizures during kindling. In fact, there is a direct study reporting basolateral amygdale kindling suppressing development of LTP in hippocampal CA1 and lateral amygdale between schaffer collaterals and afferents running with in lateral amygdale respectively, 48 hours after last kindling stimulation (Schubert et al, 2005). Thus, whether LTP induction/inhibition by early life stress directly relate increased vulnerability to limbic epileptogenensis by ELS is still not clear. Further studies directly correlating early life stress with LTP induction in pathways of kindling progression would be required.
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