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Raju Metherate

Publications and source records attributed to Raju Metherate.

12 recordsLinked to original sources
PubMed2006

Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats.

Children of women who smoke cigarettes during pregnancy display cognitive deficits in the auditory-verbal domain. Clinical studies have implicated developmental exposure to nicotine, the main psychoactive ingredient of tobacco, as a probable cause of subsequent auditory deficits. To test for a causal link, we have developed an animal model to determine how neonatal nicotine exposure affects adult auditory function. In adult control rats, nicotine administered systemically (0.7 mg/kg, s.c.) enhanced the sensitivity to sound of neural responses recorded in primary auditory cortex. The effect was strongest in cortical layers 3 and 4, where there is a dense concentration of nicotinic acetylcholine receptors (nAChRs) that has been hypothesized to regulate thalamocortical inputs. In support of the hypothesis, microinjection into layer 4 of the nonspecific nAChR antagonist mecamylamine (10 microM) strongly reduced sound-evoked responses. In contrast to the effects of acute nicotine and mecamylamine in adult control animals, neither drug was as effective in adult animals that had been treated with 5 days of chronic nicotine exposure (CNE) shortly after birth. Neonatal CNE also impaired performance on an auditory-cued active avoidance task, while having little effect on basic auditory or motor functions. Thus, neonatal CNE impairs nicotinic regulation of cortical function, and auditory learning, in the adult. Our results provide evidence that developmental nicotine exposure is responsible for auditory-cognitive deficits in the offspring of women who smoke during pregnancy, and suggest a potential underlying mechanism, namely diminished function of cortical nAChRs.

Acetylcholine↗
PubMed2005

Auditory thalamocortical transmission is reliable and temporally precise.

We have used the auditory thalamocortical slice to characterize thalamocortical transmission in primary auditory cortex (ACx) of the juvenile mouse. "Minimal" stimulation was used to activate medial geniculate neurons during whole cell recordings from regular-spiking (RS cells; mostly pyramidal) and fast-spiking (FS, putative inhibitory) neurons in ACx layers 3 and 4. Excitatory postsynaptic potentials (EPSPs) were considered monosynaptic (thalamocortical) if they met three criteria: low onset latency variability (jitter), little change in latency with increased stimulus intensity, and little change in latency during a high-frequency tetanus. Thalamocortical EPSPs were reliable (probability of postsynaptic responses to stimulation was approximately 1.0) as well as temporally precise (low jitter). Both RS and FS neurons received thalamocortical input, but EPSPs in FS cells had faster rise times, shorter latencies to peak amplitude, and shorter durations than EPSPs in RS cells. Thalamocortical EPSPs depressed during repetitive stimulation at rates (2-300 Hz) consistent with thalamic spike rates in vivo, but at stimulation rates > or = 40 Hz, EPSPs also summed to activate N-methyl-D-aspartate receptors and trigger long-lasting polysynaptic activity. We conclude that thalamic inputs to excitatory and inhibitory neurons in ACx activate reliable and temporally precise monosynaptic EPSPs that in vivo may contribute to the precise timing of acoustic-evoked responses.

2-Amino-5-phosphonovalerate↗
PubMed2005

Spectral integration in auditory cortex: mechanisms and modulation.

Auditory cortex contributes to the processing and perception of spectrotemporally complex stimuli. However, the mechanisms by which this is accomplished are not well understood. In this review, we examine evidence that single cortical neurons receive input covering much of the audible spectrum. We then propose an anatomical framework by which spectral information converges on single neurons in primary auditory cortex, via a combination of thalamocortical and intracortical "horizontal" pathways. By its nature, the framework confers sensitivity to specific, spectrotemporally complex stimuli. Finally, to address how spectral integration can be regulated, we show how one neuromodulator, acetylcholine, could act within the hypothesized framework to alter integration in single neurons. The results of these studies promote a cellular understanding of information processing in auditory cortex.

Acetylcholine↗
PubMed2004

Intracortical pathways determine breadth of subthreshold frequency receptive fields in primary auditory cortex.

To examine the basis of frequency receptive fields in auditory cortex (ACx), we have recorded intracellular (whole cell) and extracellular (local field potential, LFP) responses to tones in anesthetized rats. Frequency receptive fields derived from excitatory postsynaptic potentials (EPSPs) and LFPs from the same location resembled each other in terms of characteristic frequency (CF) and breadth of tuning, suggesting that LFPs reflect local synaptic (including subthreshold) activity. Subthreshold EPSP and LFP receptive fields were remarkably broad, often spanning five octaves (the maximum tested) at moderate intensities (40-50 dB above threshold). To identify receptive-field features that are generated intracortically, we microinjected the GABA(A) receptor agonist muscimol (0.2-5.1 mM, 1-5 microl) into ACx. Muscimol dramatically reduced LFP amplitude and reduced receptive-field bandwidth, implicating intracortical contributions to these features but had lesser effects on CF response threshold or onset latency, suggesting minimal loss of thalamocortical input. Reversal of muscimol's inhibition preferentially at the recording site by diffusion from the recording pipette of the GABA(A) receptor antagonist picrotoxin (0.01-100 microM) disinhibited responses to CF stimuli more than responses to spectrally distant, non-CF stimuli. We propose that thalamocortical and intracortical pathways preferentially contribute to responses evoked by CF and non-CF stimuli, respectively, and that intracortical projections linking frequency representations determine the breadth of receptive fields in primary ACx. Broad, subthreshold receptive fields may distinguish ACx from subcortical auditory relay nuclei, promote integrated responses to spectrotemporally complex stimuli, and provide a substrate for plasticity of cortical receptive fields and maps.

Acoustic Stimulation↗
PubMed2003

Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.

The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-transgenic model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.

Alzheimer Disease↗
PubMed2003

Spectral interactions, but no mismatch negativity, in auditory cortex of anesthetized rat.

We used an 'oddball' stimulation paradigm to evoke epidural, event-related potentials over auditory cortex in urethane/xylazine-anesthetized rats, in order to study the neural mechanisms underlying the mismatch negativity (MMN). Oddball stimulus sets included deviants (10 kHz, 10% probability) and one of six standards that ranged from 1.25 to 9.75 kHz (overall stimulus rate 2/s). Controls included 'reference' responses (10 kHz, stimulus rate 1/5 s) obtained before and after each oddball set. We found that the deviant-evoked response was modified by the preceding standards, and the degree of modification varied systematically with the spectral separation between the standard and deviant. However, the modification was apparent relative to the reference, rather than relative to the standard (as with the MMN), and did not resemble the MMN. In fact, we found no evidence for the MMN in this preparation.

Acoustic Stimulation↗
PubMed2003

Regulation of glutamate synapses by nicotinic acetylcholine receptors in auditory cortex.

Acetylcholine plays an important role in regulating the processing of sensory stimuli, and understanding its specific cellular actions is critical to understanding how sensory cortex develops and functions in different behavioral states. Here we review recent work on the cellular effects of nicotinic receptor activation in auditory cortex and describe how these actions could affect systems-level auditory function. In particular, we describe a novel function of nicotinic acetylcholine receptors to regulate glutamate synapses containing N-methyl-D-aspartate receptors during early postnatal development. The transient regulation of developing glutamate synapses also defines a window of vulnerability during which exposure to exogenous nicotine disrupts synapse development. Thus, it appears that nicotinic regulation of glutamate synapses is a critical feature of auditory cortex development.

Animals↗
PubMed2002

Postnatal development of NR2A and NR2B mRNA expression in rat auditory cortex and thalamus.

Sensory cortex in the rat undergoes rapid postnatal development, especially following the onset of sensory function during so-called "critical periods." To investigate potential mechanisms in the auditory forebrain involving different NMDA receptor subunits, we have used in situ hybridization to determine expression patterns of NR2A and NR2B mRNA at postnatal days 4, 10, 13, 18, 25, and adult. In auditory cortex, NR2A mRNA expression is initially weak but increases rapidly over approximately 2 weeks. NR2B mRNA levels are initially high and remain high. For both subunits, expression tends to be highest in superficial layers of the cortex (except layer 1). Expression is weaker in the auditory thalamus (medial geniculate). Initially, NR2A mRNA expression is very low, whereas NR2B mRNA expression is moderate; both levels increase over approximately 2 weeks. Among medial geniculate subdivisions, NR2A mRNA expression occurs preferentially in the medial division, whereas NR2B mRNA expression is strongest in the ventral division. For auditory cortex and thalamus, NR2A and NR2B mRNA expression peaks about 1 week after the onset of hearing before declining slightly into adulthood. The heterogeneous distribution of NMDAR subunit mRNA throughout development may play a role in auditory forebrain development and function.

Aging↗
PubMed2002

Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain.

Chronic nicotine exposure (CNE) can alter brain development and is thought to produce deficits in auditory function. Previously, we found that CNE during the second postnatal week, but not before or after, increases the duration of excitatory postsynaptic potentials (EPSPs) mediated by N-methyl-D-aspartate receptors (NMDARs) in rat auditory cortex. It was proposed that a potential mechanism underlying increased EPSP duration could be over-stimulation of presynaptic nicotinic acetylcholine receptors, leading to prolonged glutamate release. Since glutamatergic activity regulates levels of postsynaptic NMDAR subunits, here we examine the effects of CNE on mRNA expression for the NR2A and NR2B subunits in auditory cortex and thalamus. Two days of CNE (postnatal days 8-9), produced no effects, but 5 days (postnatal days 8-12) enhanced cortical NR2A mRNA levels and reduced thalamic NR2B mRNA levels for up to 2 weeks. These effects are consistent with the hypothesis that CNE during a postnatal critical period disrupts auditory cortex development by over-stimulating glutamatergic synapses.

Aging↗
PubMed2002

Auditory thalamocortical synaptic transmission in vitro.

To facilitate an understanding of auditory thalamocortical mechanisms, we have developed a mouse brain-slice preparation with a functional connection between the ventral division of the medial geniculate (MGv) and the primary auditory cortex (ACx). Here we present the basic characteristics of the slice in terms of physiology (intracellular and extracellular recordings, including current source density analysis), pharmacology (including glutamate receptor involvement), and anatomy (gross anatomy, Nissl, parvalbumin immunocytochemistry, and tract tracing with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Thalamocortical transmission in this preparation (the "primary" slice) involves both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid/kainate and N-methyl-D-aspartate-type glutamate receptors that appear to mediate monosynaptic inputs to layers 3-4 of ACx. MGv stimulation also initiates disynaptic inhibitory postsynaptic potentials and longer-duration intracortical, polysynaptic activity. Important differences between responses elicited by MGv versus conventional columnar ("on-beam") stimulation emphasize the necessity of thalamic activation to infer thalamocortical mechanisms. We also introduce a second slice preparation, the "shell" slice, obtained from the brain region immediately ventral to the primary slice, that may contain a nonprimary thalamocortical pathway to temporal cortex. In the shell slice, stimulation of the thalamus or the region immediately ventral to it appears to produce fast activation of synapses in cortical layer 1 followed by robust intracortical polysynaptic activity. The layer 1 responses may result from orthodromic activation of nonprimary thalamocortical pathways; however, a plausible alternative could involve antidromic activation of corticotectal neurons and their layer 1 collaterals. The primary and shell slices will provide useful tools to investigate mechanisms of information processing in the ACx.

Action Potentials↗
PubMedDate not supplied

Nicotinic acetylcholine receptors in sensory cortex.

Acetylcholine release in sensory neocortex contributes to higher-order sensory function, in part by activating nicotinic acetylcholine receptors (nAChRs). Molecular studies have revealed a bewildering array of nAChR subtypes and cellular actions; however, there is some consensus emerging about the major nAChR subtypes and their functions in sensory cortex. This review first describes the systems-level effects of activating nAChRs in visual, somatosensory, and auditory cortex, and then describes, as far as possible, the underlying cellular and synaptic mechanisms. A related goal is to examine if sensory cortex can be considered a model system for cortex in general, because the use of sensory stimuli to activate neural circuits physiologically is helpful for understanding mechanisms of systems-level function and plasticity. A final goal is to highlight the emerging role of nAChRs in developing sensory cortex, and the adverse impact of early nicotine exposure on subsequent sensory-cognitive function.

Animals↗