Abstract
The aging process eventually cause a breakdown in critical synaptic plasticity and connectivity leading to deficits in memory function. The olfactory bulb (OB) and the hippocampus, both regions of the brain considered critical for the processing of odors and spatial memory, are commonly affected by aging. Using an aged wild-type C57B/6 mouse model, we sought to define the effects of aging on hippocampal plasticity and the integrity of cortical circuits. Specifically, we measured the long-term potentiation of high-frequency stimulation (HFS-LTP) at the Shaffer-Collateral CA1 pyramidal synapses. Next, local field potential (LFP) spectra, phase-amplitude theta-gamma coupling (PAC), and connectivity through coherence were assessed in the olfactory bulb, frontal and entorhinal cortices, CA1, and amygdala circuits. The OB of aged mice showed a significant increase in the number of histone H2AX-positive neurons, a marker of DNA damage. While the input-output relationship measure of basal synaptic activity was found not to differ between young and aged mice, a pronounced decline in the slope of field excitatory postsynaptic potential (fEPSP) and the population spike amplitude (PSA) were found in aged mice. Furthermore, aging was accompanied by deficits in gamma network oscillations, a shift to slow oscillations, reduced coherence and theta-gamma PAC in the OB circuit. Thus, while the basal synaptic activity was unaltered in older mice, impairment in hippocampal synaptic transmission was observed only in response to HFS. However, age-dependent alterations in neural network appeared spontaneously in the OB circuit, suggesting the neurophysiological basis of synaptic deficits underlying olfactory processing. Taken together, the results highlight the sensitivity and therefore potential use of LFP quantitative network oscillations and connectivity at the OB level as objective electrophysiological markers that will help reveal specific dysfunctional circuits in aging-related neurodegeneration studies.
Highlights
Aging is the leading risk factor, which promotes a large class of neurodegenerative brain diseases that are feared such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1,2,3]
Wake local field potential (LFP) recoded from the olfactory bulb (OB) of both young and aged animals showed a peak in the gamma frequency oscillations; aged mice showed significant reduction in relative power at cluster correspondent to this peak, driven by frequencies between 48 and 73 Hz (Figure 2(a), bottom middle curve plot), which could be seen using more traditional two-sample t-test for a total relative gamma power in the interval of 30-80 Hz (p = 0:01, Figure 2(a), bottom right bar plot)
Using threshold-free cluster enhancement (TFCE) analysis at the entorhinal cortex (EC) network, a decrease with age in the relative power was found at clusters, driven by frequencies between 49-54 Hz, 60-67 Hz, 68-72 Hz, 7576 Hz, and 78-80 Hz (Figure 2(b), bottom middle curve plot), which could be seen in a reduction in total relative gamma power in the interval of 30-80 Hz with two-sample t-test (p = 0:02, Figure 2(b), bottom right bar plot)
Summary
Aging is the leading risk factor, which promotes a large class of neurodegenerative brain diseases that are feared such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1,2,3]. The aging impacts functional aspects of all the organs and biological pathways resulting in protein aggregations, early synapse damage, and selective neural network dysfunction. These changes make the brain more susceptible to augmenting amyloidogenic metabolism of APP, promoting the toxicity of Aβ oligomers, enhancing the hyperphosphorylation of tau, and accelerating the formation of neurofibril tangles or synucleopathy [4,5,6]. Synaptic plasticity, which is the ability of synapses to strengthen (long-term potentiation LTP) and weaken (long-term depression LTD) over time in response to increases and decreases in their activity, plays a major role in the persistent long-term changes associated with learning, memory, and cognitive functions. The natural processes of aging damage and destroy synaptic connectivity, leading to a decline in normal synaptic plasticity mechanisms and providing a likely neural basis for the decline in memory and cognition associated with age [8]
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