Amin Shakhawat

All Publications

• Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome. bioRxiv : the preprint server for biology Shakhawat, A. M., Foltz, J. G., Nance, A. B., Bhateja, J., Raymond, J. L. 2023

  Abstract

  The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments may result from saturation of the plasticity mechanism making it unavailable to be recruited at the appropriate synapses to support learning (Nguyen-Vu et al., 2017). This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here we extend this work by testing predictions of the saturation hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on an oculomotor learning task in which PF-Purkinje cell LTD has been implicated, with no impairment on an LTD-independent oculomotor learning task. Consistent with the saturation hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficit in L7-Fmr1 KO mice. These results support the hypothesis that the enhancement of synaptic plasticity can lead to its saturation in vivo and inability to support learning, providing a novel mechanistic perspective that could inform the development of new clinical approaches for autism and other disorders of the nervous system.

  View details for DOI 10.1101/2023.10.05.561013

  View details for PubMedID 37873217

  View details for PubMedCentralID PMC10592955

• Population calcium responses of Purkinje cells in the oculomotor cerebellum driven by non-visual input. Journal of neurophysiology Fanning, A., Shakhawat, A., Raymond, J. L. 2021

  Abstract

  The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by non-visual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and non-visual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this non-visual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and non-visual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning.

  View details for DOI 10.1152/jn.00715.2020

  View details for PubMedID 34346783

• Using Molecular Biology to Address Locus Coeruleus Modulation of Hippocampal Plasticity and Learning: Progress and Pitfalls HANDBOOK OF IN VIVO NEURAL PLASTICITY TECHNIQUES: A SYSTEMS NEUROSCIENCE APPROACH TO THE NEURAL BASIS OF MEMORY AND COGNITION Harley, C. W., Shakhawat, A. D., Quinlan, M. L., Carew, S. J., Walling, S. G., Yuan, Q., Martin, G. M., ManahanVaughan, D. 2018; 28: 349-364

  View details for DOI 10.1016/B978-0-12-812028-6.00019-7

  View details for Web of Science ID 000469916000020

• Arc-Expressing Neuronal Ensembles Supporting Pattern Separation Require Adrenergic Activity in Anterior Piriform Cortex: An Exploration of Neural Constraints on Learning JOURNAL OF NEUROSCIENCE Shakhawat, A. D., Gheidi, A., MacIntyre, I. T., Walsh, M. L., Harley, C. W., Yuan, Q. 2015; 35 (41): 14070-14075

  Abstract

  Arc ensembles in adult rat olfactory bulb (OB) and anterior piriform cortex (PC) were assessed after discrimination training on highly similar odor pairs. Nonselective α- and β-adrenergic antagonists or saline were infused in the OB or anterior PC during training. OB adrenergic blockade slowed, but did not prevent, odor discrimination learning. After criterion performance, Arc ensembles in anterior piriform showed enhanced stability for the rewarded odor and pattern separation for the discriminated odors as described previously. Anterior piriform adrenergic blockade prevented acquisition of similar odor discrimination and of OB ensemble changes, even with extended overtraining. Mitral and granule cell Arc ensembles in OB showed enhanced stability for rewarded odor only in the saline group. Pattern separation was not seen in the OB. Similar odor discrimination co-occurs with increased stability in rewarded odor representations and pattern separation to reduce encoding overlap. The difficulty of similar discriminations may relate to the necessity to both strengthen rewarded representations and weaken overlap across similar representations.We show for the first time that adrenoceptors in anterior piriform cortex (aPC) must be engaged for adult rats to learn to discriminate highly similar odors. Loss of adrenergic activation in olfactory bulb (OB) slows, but does not prevent, discrimination learning. Both increased stability of the rewarded odor representation and increased pattern separation of the rewarded and unrewarded odors in aPC accompany successful discrimination. In the OB, rewarded odors increase in ensemble stability, but there is no evidence of pattern separation. We suggest that the slow acquisition of similar odor discriminations is related to the differing plasticity requirements for increased stability and pattern separation.

  View details for DOI 10.1523/JNEUROSCI.2690-15.2015

  View details for Web of Science ID 000366051800026

  View details for PubMedID 26468206

  View details for PubMedCentralID PMC6608176

• Visualizing the Engram: Learning Stabilizes Odor Representations in the Olfactory Network JOURNAL OF NEUROSCIENCE Shalthawat, A. D., Gbeidi, A., Hou, Q., Dhillon, S. K., Marrone, D. F., Harley, C. W., Yuan, Q. 2014; 34 (46): 15394-15401

  Abstract

  The nature of memory is a central issue in neuroscience. How does our representation of the world change with learning and experience? Here we use the transcription of Arc mRNA, which permits probing the neural representations of temporally separated events, to address this in a well characterized odor learning model. Rat pups readily associate odor with maternal care. In pups, the lateralized olfactory networks are independent, permitting separate training and within-subject control. We use multiday training to create an enduring memory of peppermint odor. Training stabilized rewarded, but not nonrewarded, odor representations in both mitral cells and associated granule cells of the olfactory bulb and in the pyramidal cells of the anterior piriform cortex. An enlarged core of stable, likely highly active neurons represent rewarded odor at both stages of the olfactory network. Odor representations in anterior piriform cortex were sparser than typical in adult rat and did not enlarge with learning. This sparser representation of odor is congruent with the maturation of lateral olfactory tract input in rat pups. Cortical representations elsewhere have been shown to be highly variable in electrophysiological experiments, suggesting brains operate normally using dynamic and network-modulated representations. The olfactory cortical representations here are consistent with the generalized associative model of sparse variable cortical representation, as normal responses to repeated odors were highly variable (∼70% of the cells change as indexed by Arc). Learning and memory modified rewarded odor ensembles to increase stability in a core representational component.

  View details for DOI 10.1523/JNEUROSCI.3396-14.2014

  View details for Web of Science ID 000345220900027

  View details for PubMedID 25392506

  View details for PubMedCentralID PMC6608445

• Arc Visualization of Odor Objects Reveals Experience-Dependent Ensemble Sharpening, Separation, and Merging in Anterior Piriform Cortex in Adult Rat JOURNAL OF NEUROSCIENCE Shakhawat, A., Harley, C. W., Yuan, Q. 2014; 34 (31): 10206-10210

  Abstract

  Visualization using the immediate early gene Arc revealed sparser and more robust odor representations in the anterior piriform cortex of adult rats when odor was associated with water reward over 2-3 d. Rewarded odor "mixtures" resulted in rats responding to either component odor similarly, and, correspondingly, the odor representations became more similar as indexed by increased overlap in piriform Arc-expressing (Arc(+)) pyramidal neurons. The increased overlap was consistent with the rats' generalization from component odors. Discriminating among highly similar odor mixtures for reward led to increased differentiation of the neural representations as indexed by a reduction in overlap for piriform Arc(+) pyramidal neurons after training. Similar odor mixture discrimination also required more trials to criterion. The visible reduction in the overlap of odor representations indexes pattern separation. The Arc visualization of odor representations in the anterior piriform network suggests that odor objects are widely distributed representations and can be rapidly modified by reward training in adult rats. We suggest that dynamic changes such as those observed here in piriform odor encoding are at the heart of perceptual learning and reflect the continuing plastic nature of mature associative cortex as an outcome of successful problem solving.

  View details for DOI 10.1523/JNEUROSCI.1942-14.2014

  View details for Web of Science ID 000341009500006

  View details for PubMedID 25080582

  View details for PubMedCentralID PMC6608274

• Mechanisms Underlying Early Odor Preference Learning in Rats ODOR MEMORY AND PERCEPTION Yuan, Q., Shakhawat, A. D., Harley, C. W., Barkai, E., Wilson, D. A. 2014; 208: 115-156

  Abstract

  Early odor preference training in rat pups produces behavioral preferences that last from hours to lifetimes. Here, we discuss the molecular and circuitry changes we have observed in the olfactory bulb (OB) and in the anterior piriform cortex (aPC) following odor training. For normal preference learning, both structures are necessary, but learned behavior can be initiated by initiating local circuit change in either structure. Our evidence relates dynamic molecular and circuit changes to memory duration and storage localization. Results using this developmental model are consistent with biological memory theories implicating N-methyl-D-aspartate (NMDA) receptors and β-adrenoceptors, and their associated cascades, in memory induction and consolidation. Finally, our examination of the odor preference model reveals a primary role for increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor synaptic strength, and in network strength, in the creation and maintenance of preference memory in both olfactory structures.

  View details for DOI 10.1016/B978-0-444-63350-7.00005-X

  View details for Web of Science ID 000349695500006

  View details for PubMedID 24767481

• Olfactory bulb alpha(2)-adrenoceptor activation promotes rat pup odor-preference learning via a cAMP-independent mechanism LEARNING & MEMORY Shakhawat, A. D., Harley, C. W., Yuan, Q. 2012; 19 (11): 499-502

  Abstract

  In this study, three lines of evidence suggest a role for α(2)-adrenoreceptors in rat pup odor-preference learning: olfactory bulb infusions of the α(2)-antagonist, yohimbine, prevents learning; the α(2)-agonist, clonidine, paired with odor, induces learning; and subthreshold clonidine paired with subthreshold β-adrenoceptor activation also recruits learning. Increased mitral cell layer pCREB occurs with clonidine-infusion, but cAMP is not increased. Similar results using a GABAa-antagonist suggest that disinhibition may support clonidine-induced learning. We suggest that norepinephrine can act through multiple bulbar adrenoceptor subtypes to induce odor learning and that cAMP-dependent, as well as cAMP-independent, signals may act as unconditioned stimuli.

  View details for DOI 10.1101/lm.027359.112

  View details for Web of Science ID 000311409100001

  View details for PubMedID 23071064