Biomedical subjects

Michael M Merzenich

Publications and source records attributed to Michael M Merzenich.

At least 19 recordsLinked to original sources

PubMed2007

Critical period window for spectral tuning defined in the primary auditory cortex (A1) in the rat.

Experience-dependent plasticity during development results in the emergence of highly adapted representations of the external world in the adult brain. Previous studies have convincingly shown that the primary auditory cortex (A1) of the rat possesses a postnatal period of sensory input-driven plasticity but its precise timing (onset, duration, end) has not been defined. In the present study, we examined the effects of pure-tone exposure on the auditory cortex of developing rat pups at different postnatal ages with a high temporal resolution. We found that pure-tone exposure resulted in profound, persistent alterations in sound representations in A1 only if the exposure occurred during a brief period extending from postnatal day 11 (P11) to P13. We also found that postnatal sound exposure in this epoch led to striking alterations in the cortical representation of sound intensity.

Aging↗

PubMed2006

Experience-dependent adult cortical plasticity requires cognitive association between sensation and reward.

We tested the involvement of cognition in adult experience-dependent neuroplasticity using primate cortical implants. In a prior study, learning an operant sensory discrimination increased cortical excitability and target selectivity. Here, the prior task was separated into three behavioral phases. First, naive animals were exposed to stimulus-reward pairings from the prior study. These yoked animals did not have to discriminate to be rewarded and did not learn the discrimination. The plasticity observed in the prior study did not occur. Second, the animals were classically conditioned to discriminate the same stimuli in a simplified format. Learning was accompanied by increased sensory response strength and an increased range of sensory inputs eliciting responses. The third study recreated the original operant discrimination, and selectivity for task targets increased. These studies demonstrate that cognitive association between sensory stimuli and reinforcers accompanies adult experience-dependent cortical plasticity and suggest that selectivity in representation and action are linked.

Acoustic Stimulation↗

PubMed2006

Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study.

Normal aging is associated with progressive functional losses in perception, cognition, and memory. Although the root causes of age-related cognitive decline are incompletely understood, psychophysical and neuropsychological evidence suggests that a significant contribution stems from poorer signal-to-noise conditions and down-regulated neuromodulatory system function in older brains. Because the brain retains a lifelong capacity for plasticity and adaptive reorganization, dimensions of negative reorganization should be at least partially reversible through the use of an appropriately designed training program. We report here results from such a training program targeting age-related cognitive decline. Data from a randomized, controlled trial using standardized measures of neuropsychological function as outcomes are presented. Significant improvements in assessments directly related to the training tasks and significant generalization of improvements to nonrelated standardized neuropsychological measures of memory (effect size of 0.25) were documented in the group using the training program. Memory enhancement appeared to be sustained after a 3-month no-contact follow-up period. Matched active control and no-contact control groups showed no significant change in memory function after training or at the 3-month follow-up. This study demonstrates that intensive, plasticity-engaging training can result in an enhancement of cognitive function in normal mature adults.

Adult↗

PubMed2006

Perceptual learning directs auditory cortical map reorganization through top-down influences.

The primary sensory cortex is positioned at a confluence of bottom-up dedicated sensory inputs and top-down inputs related to higher-order sensory features, attentional state, and behavioral reinforcement. We tested whether topographic map plasticity in the adult primary auditory cortex and a secondary auditory area, the suprarhinal auditory field, was controlled by the statistics of bottom-up sensory inputs or by top-down task-dependent influences. Rats were trained to attend to independent parameters, either frequency or intensity, within an identical set of auditory stimuli, allowing us to vary task demands while holding the bottom-up sensory inputs constant. We observed a clear double-dissociation in map plasticity in both cortical fields. Rats trained to attend to frequency cues exhibited an expanded representation of the target frequency range within the tonotopic map but no change in sound intensity encoding compared with controls. Rats trained to attend to intensity cues expressed an increased proportion of nonmonotonic intensity response profiles preferentially tuned to the target intensity range but no change in tonotopic map organization relative to controls. The degree of topographic map plasticity within the task-relevant stimulus dimension was correlated with the degree of perceptual learning for rats in both tasks. These data suggest that enduring receptive field plasticity in the adult auditory cortex may be shaped by task-specific top-down inputs that interact with bottom-up sensory inputs and reinforcement-based neuromodulator release. Top-down inputs might confer the selectivity necessary to modify a single feature representation without affecting other spatially organized feature representations embedded within the same neural circuitry.

Acoustic Stimulation↗

PubMed2006

Severe hearing loss in Dlxl mutant mice.

The Dlx homeobox gene family participates in regulating middle and inner ear development. A significant role for Dlxl, in particular,has been demonstrated in the development of the middle ear ossicles, but the functional consequences of Dlx.l gene mutation on hearing thresholds has not been assessed. The present study characterizes auditory brainstem responses to click and tonal stimuli in a non-lethal variant of a Dlxl gene knockout. We found that peripheral hearing thresholds for click and tonal stimuli were significantly elevated in homozygous Dlxl knockout (Dlxl-/ ) compared to both heterozygous (Dlxl+/ ) and wild type (Dlxl+/+) mice. Thus, abnormal mor-phogenesis of the incus and stapes that has been documented previously with histological measures is now known to result in a severe peripheral hearing deficit.

Animals↗

PubMed2006

Brain plasticity and functional losses in the aged: scientific bases for a novel intervention.

Aging is associated with progressive losses in function across multiple systems, including sensation, cognition, memory, motor control, and affect. The traditional view has been that functional decline in aging is unavoidable because it is a direct consequence of brain machinery wearing down over time. In recent years, an alternative perspective has emerged, which elaborates on this traditional view of age-related functional decline. This new viewpoint--based upon decades of research in neuroscience, experimental psychology, and other related fields--argues that as people age, brain plasticity processes with negative consequences begin to dominate brain functioning. Four core factors--reduced schedules of brain activity, noisy processing, weakened neuromodulatory control, and negative learning--interact to create a self-reinforcing downward spiral of degraded brain function in older adults. This downward spiral might begin from reduced brain activity due to behavioral change, from a loss in brain function driven by aging brain machinery, or more likely from both. In aggregate, these interrelated factors promote plastic changes in the brain that result in age-related functional decline. This new viewpoint on the root causes of functional decline immediately suggests a remedial approach. Studies of adult brain plasticity have shown that substantial improvement in function and/or recovery from losses in sensation, cognition, memory, motor control, and affect should be possible, using appropriately designed behavioral training paradigms. Driving brain plasticity with positive outcomes requires engaging older adults in demanding sensory, cognitive, and motor activities on an intensive basis, in a behavioral context designed to re-engage and strengthen the neuromodulatory systems that control learning in adults, with the goal of increasing the fidelity, reliability, and power of cortical representations. Such a training program would serve a substantial unmet need in aging adults. Current treatments directed at age-related functional losses are limited in important ways. Pharmacological therapies can target only a limited number of the many changes believed to underlie functional decline. Behavioral approaches focus on teaching specific strategies to aid higher order cognitive functions, and do not usually aspire to fundamentally change brain function. A brain-plasticity-based training program would potentially be applicable to all aging adults with the promise of improving their operational capabilities. We have constructed such a brain-plasticity-based training program and conducted an initial randomized controlled pilot study to evaluate the feasibility of its use by older adults. A main objective of this initial study was to estimate the effect size on standardized neuropsychological measures of memory. We found that older adults could learn the training program quickly, and could use it entirely unsupervised for the majority of the time required. Pre- and posttesting documented a significant improvement in memory within the training group (effect size 0.41, p<0.0005), with no significant within-group changes in a time-matched computer using active control group, or in a no-contact control group. Thus, a brain-plasticity-based intervention targeting normal age-related cognitive decline may potentially offer benefit to a broad population of older adults.

Aged↗

PubMed2005

Development of spectral and temporal response selectivity in the auditory cortex.

The mechanisms by which hearing selectivity is elaborated and refined in early development are very incompletely determined. In this study, we documented contributions of progressively maturing inhibitory influences on the refinement of spectral and temporal response properties in the primary auditory cortex. Inhibitory receptive fields (IRFs) of infant rat auditory cortical neurons were spectrally far broader and had extended over far longer duration than did those of adults. The selective refinement of IRFs was delayed relative to that of excitatory receptive fields by an approximately 2-week period that corresponded to the critical period for plasticity. Local application of a GABA(A) receptor antagonist revealed that intracortical inhibition contributes to this progressive receptive field maturation for response selectivity in frequency. Conversely, it had no effect on the duration of IRFs or successive-signal cortical response recovery times. The importance of exposure to patterned acoustic inputs was suggested when both spectral and temporal IRF maturation were disrupted in rat pups reared in continuous, moderate-intensity noise. They were subsequently renormalized when animals were returned to standard housing conditions as adults.

Animals↗

PubMed2005

Fine functional organization of auditory cortex revealed by Fourier optical imaging.

We provide an overall view of the functional tonotopic organization of the auditory cortex in the rat. We apply a recently developed technique for acquiring intrinsic signal optical maps, Fourier imaging, in the rat auditory cortex. These highly detailed maps, derived in a several-minute-long recording procedure, delineate multiple auditory cortical areas and demonstrate their shapes, sizes, and tonotopic order. Beyond the primary auditory cortex, there are at least three distinct areas with fine-scale tonotopic organization, as well as at least one additional high-frequency field. The arrangement of all of these cortical areas is consistent across subjects. The accuracy of these optical maps was confirmed by microelectrode mapping in the same subjects. This imaging method allows fast mapping of the auditory cortex at high spatial resolution comparable to that provided by conventional microelectrode technique. Although spiking activity is largely responsible for the evoked intrinsic signals, certain features of the optical signal cannot be explained by spiking activity only, and should probably be attributed to other mechanisms inducing metabolic activity, such as subthreshold membrane phenomena.

Animals↗

PubMed2005

Cortical responses in rats predict perceptual sensitivities to complex sounds.

The common assumption that perceptual sensitivities are related to neural representations of sensory stimuli has seldom been directly demonstrated. The authors analyzed the similarity of spike trains evoked by complex sounds in the rat auditory cortex and related cortical responses to performance in an auditory task. Rats initially learned to identify 2 highly different periodic, frequency-modulated sounds and then were tested with increasingly similar sounds. Rats correctly classified most novel sounds; their accuracy was negatively correlated with acoustic similarity. Rats discriminated novel sounds with slower modulation more accurately than sounds with faster modulation. This asymmetry was consistent with similarities in cortical representations of the sounds, demonstrating that perceptual sensitivities to complex sounds can be predicted from the cortical responses they evoke.

Acoustics↗

PubMed2005

Experience-dependent plasticity in S1 caused by noncoincident inputs.

Prior work has shown that coincident inputs became co-represented in somatic sensory cortex. In this study, the hypothesis that the co-representation of digits required synchronous inputs was tested, and the daily development of two-digit receptive fields was observed with cortical implants. Two adult primates detected temporal differences in tap pairs delivered to two adjacent digits. With stimulus onset asynchronies of > or = 100 ms, representations changed to include two-digit receptive fields across the first 4 wk of training. In addition, receptive fields at sites responsive to the taps enlarged more than twofold, and receptive fields at sites not responsive to the taps had no significant areal change. Further training did not increase the expression of two-digit receptive fields. Cortical responses to the taps were not dependent on the interval length. Stimuli preceding a hit, miss, false positives, and true negatives differed in the ongoing cortical rate from 50 to 100 ms after the stimulus but did not differ in the initial, principal, response to the taps. Response latencies to the emergent responses averaged 4.3 ms longer than old responses, which occurs if plasticity is cortical in origin. New response correlations developed in parallel with the new receptive fields. These data show co-representation can be caused by presentation of stimuli across a longer time window than predicted by spike-timing-dependent plasticity and suggest that increased cortical excitability accompanies new task learning.

Action Potentials↗

PubMed2004

Associative learning shapes the neural code for stimulus magnitude in primary auditory cortex.

Since the dawn of experimental psychology, researchers have sought an understanding of the fundamental relationship between the amplitude of sensory stimuli and the magnitudes of their perceptual representations. Contemporary theories support the view that magnitude is encoded by a linear increase in firing rate established in the primary afferent pathways. In the present study, we have investigated sound intensity coding in the rat primary auditory cortex (AI) and describe its plasticity by following paired stimulus reinforcement and instrumental conditioning paradigms. In trained animals, population-response strengths in AI became more strongly nonlinear with increasing stimulus intensity. Individual AI responses became selective to more restricted ranges of sound intensities and, as a population, represented a broader range of preferred sound levels. These experiments demonstrate that the representation of stimulus magnitude can be powerfully reshaped by associative learning processes and suggest that the code for sound intensity within AI can be derived from intensity-tuned neurons that change, rather than simply increase, their firing rates in proportion to increases in sound intensity.

Acoustic Stimulation↗

PubMed2004

Temporal plasticity in the primary auditory cortex induced by operant perceptual learning.

Processing of rapidly successive acoustic stimuli can be markedly improved by sensory training. To investigate the cortical mechanisms underlying such temporal plasticity, we trained rats in a 'sound maze' in which navigation using only auditory cues led to a target location paired with food reward. In this task, the repetition rate of noise pulses increased as the distance between the rat and target location decreased. After training in the sound maze, neurons in the primary auditory cortex (A1) showed greater responses to high-rate noise pulses and stronger phase-locking of responses to the stimuli; they also showed shorter post-stimulation suppression and stronger rebound activation. These improved temporal dynamics transferred to trains of pure-tone pips. Control animals that received identical sound stimulation but were given free access to food showed the same results as naive rats. We conclude that this auditory perceptual learning results in improvements in temporal processing, which may be mediated by enhanced cortical response dynamics.

Acoustic Stimulation↗

PubMed2004

Specialization of primary auditory cortex processing by sound exposure in the "critical period".

Environmental acoustic exposure to a complex tone sequence within the critical period in infant rats resulted in the emergence of large-scale, selective changes that radically altered primary auditory cortex (A1) organization. In the sound exposure-revised A1, responses were segregated into two explicit zones representing spectrally and temporally separated lower and higher frequency tone sequence progressions. Cortical neurons between these two A1 zones were poorly driven by sound stimuli. Stimulus sequence-specific ("combination-selective") responses emerged in the A1 of exposed rats. These selective representational changes induced in the critical period persisted into adulthood. These results show that the temporal order and pace of early, repetitive postnatal auditory inputs strongly affect the emergent and enduring functional organization of A1.

Animals↗

PubMed2004

Tone-evoked excitatory and inhibitory synaptic conductances of primary auditory cortex neurons.

In primary auditory cortex (AI) neurons, tones typically evoke a brief depolarization, which can lead to spiking, followed by a long-lasting hyperpolarization. The extent to which the hyperpolarization is due to synaptic inhibition has remained unclear. Here we report in vivo whole cell voltage-clamp measurements of tone-evoked excitatory and inhibitory synaptic conductances of AI neurons of the pentobarbital-anesthetized rat. Tones evoke an increase of excitatory synaptic conductance, followed by an increase of inhibitory synaptic conductance. The synaptic conductances can account for the gross time course of the typical membrane potential response. Synaptic excitation and inhibition have the same frequency tuning. As tone intensity increases, the amplitudes of synaptic excitation and inhibition increase, and the latency of synaptic excitation decreases. Our data indicate that the interaction of synaptic excitation and inhibition shapes the time course and frequency tuning of the spike responses of AI neurons.

Acoustic Stimulation↗

PubMed2003

Progressive degradation and subsequent refinement of acoustic representations in the adult auditory cortex.

Correlated neuronal activity is believed to play an important role in refining and maintaining cortical circuitry during early development. Here we provide evidence that globally and locally correlated activity mediate different forms of adult plasticity. Pulses of broad-spectrum noise were used to activate time-locked responses across large areas of the rat auditory cortex, globally synchronizing cortical activity. Brief tone pips were used to activate relatively small groups of neurons, generating locally correlated activity. Pairing pulsed noises with nucleus basalis (NB) stimulation in awake rats for 4 weeks broadened spectral tuning, disrupted tonotopic maps, and reduced spontaneous discharge correlation in the primary auditory cortex (AI), as examined under anesthesia. Those effects caused AI neurons to appear qualitatively similar to neurons in nonprimary auditory fields of naive animals. Subsequent pairing of tone pips with NB stimulation for a period of 4 weeks completely reversed these effects induced by previous noise-NB pairing. These findings further demonstrate that the adult auditory cortex retains a substantial capacity for receptive field plasticity and tonotopic map reorganization and that locally correlated activity plays an important role in plasticity in the adult, as in the developing cortex.

Acoustic Stimulation↗

PubMed2003

Reward-dependent plasticity in the primary auditory cortex of adult monkeys trained to discriminate temporally modulated signals.

Adult owl monkeys were trained to detect an increase in the envelope frequency of a sinusoidally modulated 1-kHz tone. Detection was positively correlated with the magnitude of the change in the envelope frequency. Surprisingly, neuronal responses recorded in the primary auditory cortex of trained monkeys were globally suppressed by the modulated tone. However, the contrast in neuronal responsiveness to small increases versus large increases in envelope frequencies was actually enhanced in the trained animals. The results suggest behaviorally contingent inhibitory and excitatory processes that are modulated by the probability that a particular signal predicts a reward.

Animals↗

PubMed2003

Topography and synaptic shaping of direction selectivity in primary auditory cortex.

The direction of frequency-modulated (FM) sweeps is an important temporal cue in animal and human communication. FM direction-selective neurons are found in the primary auditory cortex (A1), but their topography and the mechanisms underlying their selectivity remain largely unknown. Here we report that in the rat A1, direction selectivity is topographically ordered in parallel with characteristic frequency (CF): low CF neurons preferred upward sweeps, whereas high CF neurons preferred downward sweeps. The asymmetry of 'inhibitory sidebands', suppressive regions flanking the tonal receptive field (TRF) of the spike response, also co-varied with CF. In vivo whole-cell recordings showed that the direction selectivity already present in the synaptic inputs was enhanced by cortical synaptic inhibition, which suppressed the synaptic excitation of the non-preferred direction more than that of the preferred. The excitatory and inhibitory synaptic TRFs had identical spectral tuning, but with inhibition delayed relative to excitation. The spectral asymmetry of the synaptic TRFs co-varied with CF, as had direction selectivity and sideband asymmetry, and thus suggested a synaptic mechanism for the shaping of FM direction selectivity and its topographic ordering.

Acoustic Stimulation↗

PubMed2003

Spectrotemporal structure of receptive fields in areas AI and AAF of mouse auditory cortex.

The mouse is a promising model system for auditory cortex research because of the powerful genetic tools available for manipulating its neural circuitry. Previous studies have identified two tonotopic auditory areas in the mouse-primary auditory cortex (AI) and anterior auditory field (AAF)- but auditory receptive fields in these areas have not yet been described. To establish a foundation for investigating auditory cortical circuitry and plasticity in the mouse, we characterized receptive-field structure in AI and AAF of anesthetized mice using spectrally complex and temporally dynamic stimuli as well as simple tonal stimuli. Spectrotemporal receptive fields (STRFs) were derived from extracellularly recorded responses to complex stimuli, and frequency-intensity tuning curves were constructed from responses to simple tonal stimuli. Both analyses revealed temporal differences between AI and AAF responses: peak latencies and receptive-field durations for STRFs and first-spike latencies for responses to tone bursts were significantly longer in AI than in AAF. Spectral properties of AI and AAF receptive fields were more similar, although STRF bandwidths were slightly broader in AI than in AAF. Finally, in both AI and AAF, a substantial minority of STRFs were spectrotemporally inseparable. The spectrotemporal interaction typically appeared in the form of clearly disjoint excitatory and inhibitory subfields or an obvious spectrotemporal slant in the STRF. These data provide the first detailed description of auditory receptive fields in the mouse and suggest that although neurons in areas AI and AAF share many response characteristics, area AAF may be specialized for faster temporal processing.

Acoustic Stimulation↗