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Traces of Learning in Thalamocortical Circuits

2019; Cell Press; Volume: 103; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2019.06.020

1097-4199

Alex J. Yonk, David J. Margolis,

Advanced Memory and Neural Computing

A recent study (Audette et al., 2019Audette N.J. Bernhard S.M. Ray A. Stewart L.T. Barth A.L. Rapid plasticity of higher-order thalamocortical inputs during sensory learning.Neuron. 2019; 103: 1-15Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) demonstrates that thalamic input from the posterior medial (POm) nucleus to somatosensory cortex plays an unexpected role in plasticity resulting from associative sensory learning. POm-mediated plasticity may be critical for coordinating learning-related sensorimotor circuitry. A recent study (Audette et al., 2019Audette N.J. Bernhard S.M. Ray A. Stewart L.T. Barth A.L. Rapid plasticity of higher-order thalamocortical inputs during sensory learning.Neuron. 2019; 103: 1-15Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) demonstrates that thalamic input from the posterior medial (POm) nucleus to somatosensory cortex plays an unexpected role in plasticity resulting from associative sensory learning. POm-mediated plasticity may be critical for coordinating learning-related sensorimotor circuitry. The brain possesses a remarkable capacity to form associations between sensory stimuli and their behavioral meaning. Imagine a mouse whisking in twilight: it can quickly tell the difference (let's hope!) between the tactile sensation of a mate's soft fur compared to the rough scales of a predator. How do mice learn such sensory associations? Classic studies of the rodent whisker system have yielded important insights into the sites and mechanisms of neural plasticity. With altered sensory experience, such as whisker deprivation or overstimulation, intracortical synapses (between cortical neurons) in primary somatosensory (S1) barrel cortex have been largely implicated as the first sites of plasticity (Feldman and Brecht, 2005Feldman D.E. Brecht M. Map plasticity in somatosensory cortex.Science. 2005; 310: 810-815Crossref PubMed Scopus (439) Google Scholar). However, recent evidence has shown that thalamocortical synapses (between thalamus and cortex) are also capable of plasticity (Oberlaender et al., 2012Oberlaender M. Ramirez A. Bruno R.M. Sensory experience restructures thalamocortical axons during adulthood.Neuron. 2012; 74: 648-655Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, Gambino et al., 2014Gambino F. Pagès S. Kehayas V. Baptista D. Tatti R. Carleton A. Holtmaat A. Sensory-evoked LTP driven by dendritic plateau potentials in vivo.Nature. 2014; 515: 116-119Crossref PubMed Scopus (156) Google Scholar). Whether thalamocortical synapses undergo synaptic changes during learning and, if so, which thalamocortical pathways have remained a mystery. Neurons of the ventral posterior medial (VPM) thalamus respond best to single-whisker stimulation and primarily project to layers 4 and deeper layers of the S1 barrel cortex, defining the classical lemniscal pathway for transmission of sensory information (Figure 1A). In contrast, neurons of the posterior medial (POm) thalamus respond best to multi-whisker stimulation and project to cortical layers 1 and 5a (Figure 1A) (Bureau et al., 2006Bureau I. von Saint Paul F. Svoboda K. Interdigitated paralemniscal and lemniscal pathways in the mouse barrel cortex.PLoS Biol. 2006; 4: e382Crossref PubMed Scopus (195) Google Scholar). In addition, POm receives more top-down input from sensory and motor cortical areas and is therefore considered a higher-order thalamic nucleus. The possibility that VPM and POm thalamocortical synapses undergo learning-related plasticity has not been tested. However, recent studies have indicated that POm thalamocortical pathways have an enhanced capacity for inducing S1 synaptic strengthening compared to VPM (Gambino et al., 2014Gambino F. Pagès S. Kehayas V. Baptista D. Tatti R. Carleton A. Holtmaat A. Sensory-evoked LTP driven by dendritic plateau potentials in vivo.Nature. 2014; 515: 116-119Crossref PubMed Scopus (156) Google Scholar, Williams and Holtmaat, 2019Williams L.E. Holtmaat A. Higher-order thalamocortical inputs gate synaptic long-term potentiation via disinhibition.Neuron. 2019; 101: 91-102.e4Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). The study by Audette et al., 2019Audette N.J. Bernhard S.M. Ray A. Stewart L.T. Barth A.L. Rapid plasticity of higher-order thalamocortical inputs during sensory learning.Neuron. 2019; 103: 1-15Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, recently published in Neuron, investigated thalamocortical plasticity mechanisms by measuring detailed physiological properties of S1 barrel cortex neurons after mice learned an associative sensory task. The authors developed an automated homecage training paradigm that paired water delivery from the in-cage spout with air puff stimulation of the right-side whiskers. After 24 h and hundreds of trials, 75% of the mice showed anticipatory licking within a 300-ms time window after the air puff and before water delivery, as expected for a conditional sensory stimulus. The high-throughput nature of this paradigm allowed the authors to collect a large dataset of the physiological effects of 24 or 48 h of sensory-association training. The inclusion of control groups that received the same water and whisker stimuli, but in a decoupled fashion, further permitted the authors to distinguish between learning and sensory stimulation alone, which under certain conditions can also induce lasting cortical plasticity (Gambino et al., 2014Gambino F. Pagès S. Kehayas V. Baptista D. Tatti R. Carleton A. Holtmaat A. Sensory-evoked LTP driven by dendritic plateau potentials in vivo.Nature. 2014; 515: 116-119Crossref PubMed Scopus (156) Google Scholar). To investigate learning-related synaptic changes, the authors performed ex vivo patch-clamp recordings from targeted S1 neurons in response to optogenetic stimulation of either VPM or POm synaptic inputs. This allowed Audette et al. to assess the relative contributions of each thalamic pathway in control mice and in mice trained on the task. In 24-h trained animals, POm activation produced greatly enhanced spiking responses in both L5a and L2 neurons (Figure 1B). Fascinatingly, while L5a and L2 responses were both increased in amplitude, further voltage clamp experiments revealed that only POm-L5a synapses were potentiated at 24 h. The enhanced and prolonged responses of L2 neurons were driven by direct POm-L2 input and disynaptic POm-L5-L2 connections (Figure 1B). Thus, strengthening of the POm-L5a synapse during early learning leads to reverberatory circuit effects that enhance and prolong activity in L2. With one additional day of training, synaptic strengthening also occurs at POm-L2 synapses, with POm-L5 synapses remaining at 24-h levels. Taken together, sensory associative learning initially potentiates POm-L5a synapses at 24 h, followed by POm-L2 synapses at 48 h. At both time points, POm activation evokes reverberatory activity in L2 through a combination of L5-L2 and direct POm-L2 input. Critically, no potentiation effects were seen in cells from any layer recorded in response to VPM stimulation, suggesting that the learning-related synaptic and circuit changes are specific to POm. The intrinsic physiological properties of neurons in all layers and the strength of intralaminar connections (L2-L2 and L5-L5) appeared unchanged, providing further evidence for specificity in the strengthening of POm-S1 synapses. These findings raise a number of important questions for understanding the neural circuitry of sensory learning. First, do higher-order thalamocortical pathways play a privileged role in learning- and behavior-related plasticity? The specificity of plasticity in POm compared with VPM connections with S1 is consistent with recent work (Gambino et al., 2014Gambino F. Pagès S. Kehayas V. Baptista D. Tatti R. Carleton A. Holtmaat A. Sensory-evoked LTP driven by dendritic plateau potentials in vivo.Nature. 2014; 515: 116-119Crossref PubMed Scopus (156) Google Scholar) and suggests that POm may be more closely associated with induction of S1 plasticity than VPM, possibly through disinhibitory mechanisms (Williams and Holtmaat, 2019Williams L.E. Holtmaat A. Higher-order thalamocortical inputs gate synaptic long-term potentiation via disinhibition.Neuron. 2019; 101: 91-102.e4Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). One cautionary note is that the associative learning task used by Audette et al. was relatively simplistic compared with sensory discrimination tasks that take longer to learn and require cortex for learning and performance. The mice used in the study were also relatively young (3–4 weeks old). Therefore, it will be important in future work to determine how POm and VPM thalamocortical circuitry is involved in learning more cognitively challenging sensory-guided behaviors and whether results in adult mice are consistent with the presented results. Second, POm is prominently interconnected with several brain regions in addition to S1, including motor cortex (M1) and dorsal striatum (Str) (Alloway et al., 2017Alloway K.D. Smith J.B. Mowery T.M. Watson G.D.R. Sensory Processing in the Dorsolateral Striatum: The Contribution of Thalamostriatal Pathways.Front. Syst. Neurosci. 2017; 11: 53Crossref PubMed Scopus (38) Google Scholar) (Figure 1C). Does POm function as a "hub" in the coordination of sensorimotor circuits? One intriguing possibility is that learning-related synaptic strengthening occurs at other sites of POm projections, including Str. Str plays a critical role in associative reinforcement learning, and recent work has implicated striatal inputs from thalamus, S1, and M1 in the modulation of learned sensorimotor behaviors (Díaz-Hernández et al., 2018Díaz-Hernández E. Contreras-López R. Sánchez-Fuentes A. Rodríguez-Sibrían L. Ramírez-Jarquín J.O. Tecuapetla F. The Thalamostriatal Projections Contribute to the Initiation and Execution of a Sequence of Movements.Neuron. 2018; 100: 739-752.e5Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, Lee et al., 2019Lee C.R. Yonk A.J. Wiskerke J. Paradiso K.G. Tepper J.M. Margolis D.J. Opposing Influence of Sensory and Motor Cortical Input on Striatal Circuitry and Choice Behavior.Curr. Biol. 2019; 29: 1313-1323.e5Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Determining the potential role of POm in coordination of thalamocortical, thalamostriatal, cortiocothalamic, and corticostriatal pathways will be an essential avenue for future research. A combination of techniques, including ex vivo synaptic physiology as performed by Audette et al. and in vivo recordings and manipulations, will be necessary to attain a full understanding of the activity dynamics of POm and related circuitries during learning (e.g., Tanaka et al., 2018Tanaka Y.H. Tanaka Y.R. Kondo M. Terada S.I. Kawaguchi Y. Matsuzaki M. Thalamocortical Axonal Activity in Motor Cortex Exhibits Layer-Specific Dynamics during Motor Learning.Neuron. 2018; 100: 244-258.e12Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Finally, the distinct functions of cortical layers have been an enduring mystery in neuroscience. The results of Audette et al. suggest a sequential circuitry model of thalamocortical plasticity, occurring early (within 24 h) at L5a, and later (within 48 h) at L2. This concept will guide further investigation into the roles of identified cortical cell types in learning- and sensory-guided behaviors. The Margolis laboratory is supported by the National Institutes of Health (R01NS094450), National Science Foundation (IOS-1845355), and New Jersey Commission on Brain Injury Research (CBIR16IRG032). The authors thank Margolis Lab members for helpful comments. Rapid Plasticity of Higher-Order Thalamocortical Inputs during Sensory LearningAudette et al.NeuronMay 28, 2019In BriefAudette et al. use automated training and in vitro electrophysiology to define cortical circuit changes during sensory-association learning. Pathway-specific analysis identifies higher-order thalamic inputs to sensory cortex as a site of synaptic potentiation during the earliest stages of learning. 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