Kasia M. Bieszczad

Representational gain in cortical area underlies increase of memory strength

Neuronal plasticity that develops in the cortex during learning is assumed to represent memory content, but the functions of such plasticity are actually unknown. The shift in spectral tuning in primary auditory cortex (A1) to the frequency of a tone signal is a compelling candidate for a substrate of memory because it has all of the cardinal attributes of associative memory: associativity, specificity, rapid induction, consolidation, and long-term retention. Tuning shifts increase the representational area of the signal in A1, as an increasing function of performance level, suggesting that area encodes the magnitude of acquired stimulus significance. The present study addresses the question of the specific function of learning-induced associative representational plasticity. We tested the hypothesis that specific increases in A1 representational area for an auditory signal serve the mnemonic function of enhancing memory strength for that signal. Rats were trained to bar-press for reward contingent on the presence of a signal tone (5.0 kHz), and assessed for memory strength during extinction. The amount of representational area gain for the signal frequency band was significantly positively correlated with resistance to extinction to the signal frequency in two studies that spanned the range of task difficulty. These findings indicate that specific gain in cortical representational area underlies the strength of the behaviorally-relevant contents of memory. Thus, mnemonic functions of cortical plasticity are determinable.

Extinction reveals that primary sensory cortex predicts reinforcement outcome

Primary sensory cortices are traditionally regarded as stimulus analysers. However, studies of associative learning‐induced plasticity in the primary auditory cortex (A1) indicate involvement in learning, memory and other cognitive processes. For example, the area of representation of a tone becomes larger for stronger auditory memories and the magnitude of area gain is proportional to the degree that a tone becomes behaviorally important. Here, we used extinction to investigate whether ‘behavioral importance’ specifically reflects a sound’s ability to predict reinforcement (reward or punishment) vs. to predict any significant change in the meaning of a sound. If the former, then extinction should reverse area gains as the signal no longer predicts reinforcement. Rats (n = 11) were trained to bar‐press to a signal tone (5.0 kHz) for water‐rewards, to induce signal‐specific area gains in A1. After subsequent withdrawal of reward, A1 was mapped to determine representational areas. Signal‐specific area gains, estimated from a previously established brain–behavior quantitative function, were reversed, supporting the ‘reinforcement prediction’ hypothesis. Area loss was specific to the signal tone vs. test tones, further indicating that withdrawal of reinforcement, rather than unreinforced tone presentation per se, was responsible for area loss. Importantly, the amount of area loss was correlated with the amount of extinction (r = 0.82, P < 0.01). These findings show that primary sensory cortical representation can encode behavioral importance as a signal’s value to predict reinforcement, and that the number of cells tuned to a stimulus can dictate its ability to command behavior.

Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation

Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. SIGNIFICANCE STATEMENT Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually “tuned-in” to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control “informational capture” at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.

Nicotinic acetylcholine receptors in rat forebrain that bind 18F-nifene: Relating PET imaging, autoradiography, and behavior

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound 18F‐nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory‐cognitive task. We first show negligible binding of 18F‐nifene in mice lacking the β2 nAChR subunit, consistent with previous findings that 18F‐nifene binds to α4β2* nAChRs. We then examined the distribution of 18F‐nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, 18F‐nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, 18F‐nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related 18F‐nifene binding in several forebrain regions to each animals performance on an auditory‐cued, active avoidance task. The strongest correlations with performance after 14 days training were found for 18F‐nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory‐cognitive function. Synapse, 2012.

Gamma band plasticity in sensory cortex is a signature of the strongest memory rather than memory of the training stimulus

Gamma oscillations (∼30-120Hz) are considered to be a reflection of coordinated neuronal activity, linked to processes underlying synaptic integration and plasticity. Increases in gamma power within the cerebral cortex have been found during many cognitive processes such as attention, learning, memory and problem solving in both humans and animals. However, the specificity of gamma to the detailed contents of memory remains largely unknown. We investigated the relationship between learning-induced increased gamma power in the primary auditory cortex (A1) and the strength of memory for acoustic frequency. Adult male rats (n=16) received three days (200 trials each) of pairing a tone (3.66 kHz) with stimulation of the nucleus basalis, which implanted a memory for acoustic frequency as assessed by associatively-induced disruption of ongoing behavior, viz., respiration. Post-training frequency generalization gradients (FGGs) revealed peaks at non-CS frequencies in 11/16 cases, likely reflecting normal variation in pre-training acoustic experiences. A stronger relationship was found between increased gamma power and the frequency with the strongest memory (peak of the difference between individual post- and pre-training FGGs) vs. behavioral responses to the CS training frequency. No such relationship was found for the theta/alpha band (4-15 Hz). These findings indicate that the strength of specific increased neuronal synchronization within primary sensory cortical fields can determine the specific contents of memory.

Sensory Cortical Plasticity Participates in the Epigenetic Regulation of Robust Memory Formation

Neuroplasticity remodels sensory cortex across the lifespan. A function of adult sensory cortical plasticity may be capturing available information during perception for memory formation. The degree of experience-dependent remodeling in sensory cortex appears to determine memory strength and specificity for important sensory signals. A key open question is how plasticity is engaged to induce different degrees of sensory cortical remodeling. Neural plasticity for long-term memory requires the expression of genes underlying stable changes in neuronal function, structure, connectivity, and, ultimately, behavior. Lasting changes in transcriptional activity may depend on epigenetic mechanisms; some of the best studied in behavioral neuroscience are DNA methylation and histone acetylation and deacetylation, which, respectively, promote and repress gene expression. One purpose of this review is to propose epigenetic regulation of sensory cortical remodeling as a mechanism enabling the transformation of significant information from experiences into content-rich memories of those experiences. Recent evidence suggests how epigenetic mechanisms regulate highly specific reorganization of sensory cortical representations that establish a widespread network for memory. Thus, epigenetic mechanisms could initiate events to establish exceptionally persistent and robust memories at a systems-wide level by engaging sensory cortical plasticity for gating what and how much information becomes encoded.

Contextual learning in the neurosolver

In this paper, we introduce an enhancement to the Neurosolver, a neuromorphic planner and a problem solving system. The enhanced architecture enables contextual learning. The Neurosolver was designed and tested on several problem solving and planning tasks such as re-arranging blocks and controlling a software-simulated artificial rat running in a maze. In these tasks, the Neurosolver learned temporal patterns independent of the context. However in the real world no skill is acquired in vacuum; Contextual cues are a part of every situation, and the brain can incorporate such stimuli as evidenced through experiments with live rats. Rats use cues from the environment to navigate inside mazes. The enhanced architecture of the Neurosolver accommodates similar learning.