Neuroscience. 2015 Aug 20;301:90-105. doi: 10.1016/j.neuroscience.2015.05.062.

Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD.

Moorthi P1, Premkumar P1, Priyanka R1, Jayachandran KS2, Anusuyadevi M3.

  1. Department of Biochemistry, Molecular Gerontology Laboratory, Bharathidasan University, Tiruchirappalli 620024, India.
  2. Department of Bioinformatics, Bharathidasan University, Tiruchirappalli 620024, India.
  3. Department of Biochemistry, Molecular Gerontology Laboratory, Bharathidasan University, Tiruchirappalli 620024, India. Electronic address: msanushyas2005@gmail.com.

 

Abstract

Among vertebrates hippocampus forms the major component of the brain in consolidating information from short-term memory to long-term memory. Aging is considered as the major risk factor for memory impairment in sporadic Alzheimer’s disease (SAD) like pathology. Present study thus aims at investigating whether age-specific degeneration of neuronal-circuits in hippocampal formation (neural-layout of Subiculum-hippocampus proper-dentate gyrus (DG)-entorhinal cortex (EC)) results in cognitive impairment. Furthermore, the neuroprotective effect of Resveratrol (RSV) was attempted to study in the formation of hippocampal neuronal-circuits. Radial-Arm-Maze was conducted to evaluate hippocampal-dependent spatial and learning memory in control and experimental rats. Nissl staining of frontal cortex (FC), subiculum, hippocampal-proper (CA1→CA2→CA3→CA4), DG, amygdala, cerebellum, thalamus, hypothalamus, layers of temporal and parietal lobe of the neocortex were examined for pathological changes in young and aged wistar rats, with and without RSV. Hippocampal trisynaptic circuit (EC layerII→DG→CA3→CA1) forming new memory and monosynaptic circuit (EC→CA1) that strengthen old memories were found disturbed in aged rats. Loss of Granular neuron observed in DG and polymorphic cells of CA4 can lead to decreased mossy fibers disturbing neural-transmission (CA4→CA3) in perforant pathway. Further, intensity of nissl granules (stratum lacunosum moleculare (SLM)-SR-SO) of CA3 pyramidal neurons was decreased, disturbing the communication in schaffer collaterals (CA3-CA1) during aging. We also noticed disarranged neuronal cell layer in Subiculum (presubiculum (PrS)-parasubiculum (PaS)), interfering output from hippocampus to prefrontal cortex (PFC), EC, hypothalamus, and amygdala that may result in interruption of thought processes. We conclude from our observations that poor memory performance of aged rats as evidenced through radial arm maze (RAM) analysis was due to the defect in neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) that were significantly damaged leading to memory impairment. Interestingly, RSV was observed to culminate pathological events in the hippocampal neuronal circuit during aging, proving them as potent therapeutic drug against age-associated neurodegeneration and memory loss.

KEYWORDS: RSV; SIRT1; aging; hippocampus; neurodegeneration; spreading-pathology

PMID:   26045180

 

Supplements:

Aging is a natural phenomenon that is now widely considered as one of the major risk factor for neurodegenerative diseases like Sporadic Alzheimer’s Disease (SAD). The process of aging and its interference in the neuronal circuits (that are organized into ensemble of connections) to that of SAD is not a quest in recent research & no report has ever been published in earlier decades. Distinct neurodegeneration patterns in the brain can underlie different forms of dementia, a major classical symptom for a variety of neurodegenerative diseases. If this is really the case, it is unclear about what happens to the brain, as we get older? How it contributes to changes in the morphology thereby promoting neurodegeneration remained elusive. To find answers for these questions, present study aims at investigating, age-specific anatomical changes and disturbances in the neuronal-circuits of hippocampal formation (neural-layout of Subiculum-hippocampus proper-DG-EC) and resultant cognitive impairment during aging. Detailed investigation and analysis were done on the pathological events in each region and sub-region of the young and aged rat brain, looking for a positive clue toward age-associated SAD progression. Further, neuroprotective effect of resveratrol (RSV) on age-specific pathological changes in the hippocampal neuronal-circuits were evaluated.

Aged control rats showed the incidence of reference and working memory error that measures hippocampal-dependent learning and memory to be significantly higher, suggesting defects in amygdala, thalamus and trisynaptic regions of the hippocampus. RSV as a well-known anti-aging compound, at a concentration of 20mg/kg for a period of 15 days was administrated to aged rats, expecting to extend a positive role in reversing physiological performance during aging. While RSV failed to prevent age-associated spatial learning and memory deficit. Also, the overall body weight gain that are significantly higher in aged rats, which is directly implicated in age-related risks of neurodegeneration and absolute weights of the liver, kidney and brain that were elevated during aging with gradually decreasing organ development rate (relative weight) doesn’t show any significant improvement with RSV administration. In specific, the efficiency of RSV on body-mass and organ weights maintained the overall body weight of the experimental rats but not absolute and relative weight of the organs. Age-associated decline in the growth rate, may have impact on age-associated diseases accompanied with changes in normal physiological functions. Interestingly, RSV did not exhibit any toxic side effects, rather able to improve and retain normal architecture in the liver and kidney of aged rats. This proved the potentiality of RSV in reversing complications of vital organs raising the expectations of providing a healthy lifespan that may be through the enhanced activity of homeostatic factor like SIRT1. In this line of thoughts, SIRT1 levels were assessed and found to be down regulated in hippocampus and FC of aged control rats, whereas RSV treated rats significantly increase the levels of SIRT1. These suggests that RSV may prove good against neurodegeneration.

Numerous studies have documented the connection between morphological changes and a functional decline in the central nervous system (CNS), whereas a series of pathological events that describe pathologies in network connectivity at every level of organizational units of memory formation as a possible cause of SAD-like pathology has not been described so far. Age-associated spreading pathology may cause decline in memory and raise the possibility of age-associated neurodegenerative diseases like SAD (where memory loss is an evident phenomenon). Cresyl Violet (CV) staining of various brain regions of young and aged rats with and without RSV shows an extensive loss of glutamatergic and inhibitory GABAergic neurons during aging. Moreover, Trisynaptic (EC layerII→DG→CA3→CA1) circuit forming new memory and monosynaptic circuit (EC→CA1) that strengthens old memories was disturbed. Loss of Granular neuron in DG and polymorphic cells of CA4 lead to decreased mossy fibers disturbing neural-transmission (CA4→CA3) in perforant pathway. Further, intensity of Nissl granules (SLM-SR-SO) of CA3 pyramidal neurons was decreased, disturbing the communication in Schaffer collaterals (CA3-CA1) during aging. We also noticed disarranged neuronal cell layer in Subiculum (PrS-PaS), interfering output from hippocampus to PFC, EC, Hypothalamus, and amygdala that may interrupt thinking ability (Figure. 1). Our observations conclude that neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) were disturbed at every level leading to memory impairment. These changes may raise the susceptibility ratio of the aging population toward neurodegenerative diseases like SAD. These observations led us to confirm that new memory formation and strengthening of old memories also have got disturbed resulting in the loss of episodic memory.

 

AJ fig1

Figure 1. Schematic representation showing trisynaptic and monosynaptic connections & highlights age-associated sequential pathological changes in hippocampal circuits connecting various subregions (CA1, CA2, CA3, DG and subiculum). Damages in these neuronal circuits may a possible cause of age associated memory loss.

 

Current study also tried to recover these changes using RSV as an efficacious strategy in preserving memory function during aging. Interestingly, RSV-treated aged animals were able to overcome age-associated pathological alterations with increased levels of matured neurons, prominent cytoplasmic staining, reduced dark and apoptotic neurons. Remarkably, it promotes thalamo-cortical connectivity and amygdala-hippocampus interactions. These results suggest that, RSV may extend its protection in preventing age-associated neurodegenerative diseases like SAD. On the other hand, RSV did not respond to certain age-related parameters on 15 days of treatment, where as it proved good in reverting morphological and pathological changes during aging.

Therefore, the current study implies that by increasing the dosage or duration of RSV to aged animals may extend its efficacy in culminating age-associated pathological as well as physiological changes to a greater extent. Further studies and intensive research are considered necessary to identify the molecular core of RSV in preventing pathological alterations and the behind mechanism, in way of protecting the brain from neurodegeneration.

 

Contact:

Dr. M. Anusuyadevi

Molecular Gerontology Laboratory,

Department of Biochemistry,

Bharathidasan University,

Tiruchirappalli-620024

Tamilnadu, India.

Tel.: +91 431 2407071 (Ext: 438); Fax: +91 431 2407045

E-mail address: msanushyas2005@gmail.com

Web : www.majlab.weebly.com

 

 

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