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NMDA spikes mediate amplification of inputs in the rat piriform cortex.

ABSTRACT: The piriform cortex (PCx) receives direct input from the olfactory bulb (OB) and is the brain's main station for odor recognition and memory. The transformation of the odor code from OB to PCx is profound: mitral and tufted cells in olfactory glomeruli respond to individual odorant molecules, whereas pyramidal neurons (PNs) in the PCx responds to multiple, apparently random combinations of activated glomeruli. How these 'discontinuous' receptive fields are formed from OB inputs remains unknown. Counter to the prevailing view that olfactory PNs sum their inputs passively, we show for the first time that NMDA spikes within individual dendrites can both amplify OB inputs and impose combination selectivity upon them, while their ability to compartmentalize voltage signals allows different dendrites to represent different odorant combinations. Thus, the 2-layer integrative behavior of olfactory PN dendrites provides a parsimonious account for the nonlinear remapping of the odor code from bulb to cortex.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6333441 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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NMDA spikes mediate amplification of inputs in the rat piriform cortex.

Kumar Amit A Schiff Oded O Barkai Edi E Mel Bartlett W BW Poleg-Polsky Alon A Schiller Jackie J

eLife 20181221

The piriform cortex (PCx) receives direct input from the olfactory bulb (OB) and is the brain's main station for odor recognition and memory. The transformation of the odor code from OB to PCx is profound: mitral and tufted cells in olfactory glomeruli respond to individual odorant molecules, whereas pyramidal neurons (PNs) in the PCx responds to multiple, apparently random combinations of activated glomeruli. How these 'discontinuous' receptive fields are formed from OB inputs remains unknown. ...[more]

PMID: 30575520

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Project description:BackgroundOrganophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury.MethodsTo determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate)-induced seizure. Male Sprague-Dawley rats were challenged with 1 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course.ResultsA multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined.ConclusionsThis analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will facilitate the identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure.

Project description:Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the ?-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency ?-oscillations (LF?) and high-frequency ?-oscillations (HF?) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HF? and LF? in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LF? (? 34 Hz at 32°C) in layer V and HF? (? 54 Hz) in layer III of the same cortical column. In controls, HF? and LF? were independent, and pyramidal neurons recorded in layer III were entrained by HF?, but not by LF?. Sub-anesthetic concentrations of ketamine selectively decelerated HF? by 22 Hz (EC(50)=2.7 ?M), to match the frequency of LF? in layer V. This caused phase coupling of the two ?-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LF? in layer V. PCP similarly decelerated HF? by 22 Hz (EC(50)=0.16 ?M), causing cross-layer phase coupling of ?-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HF?, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HF?. The NMDA receptor hypofunction-induced phase coupling of the normally independent ?-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HF? and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HF? could be the target for improved antipsychotic therapy.

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NMDA spikes mediate amplification of inputs in the rat piriform cortex.

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NMDA spikes mediate amplification of inputs in the rat piriform cortex.

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