Ongoing network activity often manifests as irregular fluctuations in local field potentials (LFPs), a complex mixture of multicellular synaptic currents of varying locations and extensions. Among other conditions, for synchronously firing presynaptic units to generate sizable postsynaptic LFPs, their axonal territories should overlap. We have taken advantage of anatomical regularity of the rat hippocampus and combined multiple linear recordings and spatial discrimination techniques to separate pathway-specific LFPs with enough spatial resolution to discriminate postsynaptic regions of varying activation, and to investigate their presynaptic origin, chemical nature, and spatial extension. We identified 6 main excitatory and inhibitory LFP generators with different synaptic territories in principal cells and hippocampal subfields matching anatomical pathways. Some recognized pathways did not contribute notably to LFPs. Each showed different septo-temporal spatial modules over which the field potential fluctuations were synchronous. These modules were explained by either the strong overlap of synaptic territories of coactivated afferent neurons (e.g., CA3 clusters for CA1 Schaffer LFPs), or widespread coalescence of postsynaptic territories (granule cell somatic inhibition). We also show evidence that distinct modes of afferent synchronization generate stereotyped spatial patterns of synchronous LFPs in one pathway. Thus, studying spatial coherence of pathway-specific LFPs provides remote access to the dynamics of afferent populations.
Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de-phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p-Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.
Analysis of local field potentials (LFPs) helps understand the function of the converging neuronal populations that produce the mixed synaptic activity in principal cells. Recently, using independent component analysis (ICA), we resolved ongoing hippocampal activity into several major contributions of stratified LFP-generators. Here, using pathway-specific LFP reconstruction, we isolated LFP-generators that describe the activity of Schaffer-CA1 and Perforant-Dentate excitatory inputs in the anesthetized rat. First, we applied ICA and current source density analysis to LFPs evoked by electrical subthreshold stimulation of the pathways. The results showed that pathway specific activity is selectively captured by individual components or LFP-generators. Each generator matches the known distribution of axonal terminal fields in the hippocampus and recovers the specific time course of their activation. Second, we use sparse weak electrical stimulation to prime ongoing LFPs with activity of a known origin. Decomposition of ongoing LFPs yields a few significant LFP-generators with distinct spatiotemporal characteristics for the Schaffer and Perforant inputs. Both pathways convey an irregular temporal pattern in bouts of population activity of varying amplitude. Importantly, the contribution of Schaffer and Perforant inputs to the power of raw LFPs in the hippocampus is minor (7 and 5%, respectively). The results support the hypothesis on a sparse population code used by excitatory populations in the entorhino-hippocampal system, and they validate the separation of LFP-generators as a powerful tool to explore the computational function of neuronal circuits in real time.
Sleep is a conserved behavioral state. Invertebrates typically show quiet sleep, whereas in mammals, sleep consists of periods of non-rapid-eye-movement sleep (NREMS) and REM sleep (REMS). We previously found that the transcription factor AP-2 promotes sleep in C. elegans and Drosophila. In mammals, several paralogous AP-2 transcription factors exist. Sleep-controlling genes are often conserved. However, little is known about how sleep genes evolved from controlling simpler types of sleep to govern complex mammalian sleep. Here, we studied the roles of Tfap2a and Tfap2b in sleep control in mice. Consistent with our results from C. elegans and Drosophila, the AP-2 transcription factors Tfap2a and Tfap2b also control sleep in mice. Surprisingly, however, the two AP-2 paralogs play contrary roles in sleep control. Tfap2a reduction of function causes stronger delta and theta power in both baseline and homeostasis analysis, thus indicating increased sleep quality, but did not affect sleep quantity. By contrast, Tfap2b reduction of function decreased NREM sleep time specifically during the dark phase, reduced NREMS and REMS power, and caused a weaker response to sleep deprivation. Consistent with the observed signatures of decreased sleep quality, stress resistance and memory were impaired in Tfap2b mutant animals. Also, the circadian period was slightly shortened. Taken together, AP-2 transcription factors control sleep behavior also in mice, but the role of the AP-2 genes functionally diversified to allow for a bidirectional control of sleep quality. Divergence of AP-2 transcription factors might perhaps have supported the evolution of more complex types of sleep.
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