S. Murray Sherman

Maurice Goldblatt Professor and Chairman,

Department of Neurobiology

The University of Chicago
947 E. 58th St., MC0926
Chicago, IL 60637

Email: msherman@bsd.uchicago.edu
Phone: (773) 834- 2900
Office: Abbott 316 (MC 0926)

 

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Research Statement

The research in the laboratory is directed at issues of thalamic functional organization and thalamocortical relationships. We use a broad interdisciplinary approach, attempting to answer the same or closely related questions with several different techniques. More specifically, we use neuroanatomical techniques to explore various circuits; we use in vitro recordings from brain slices to study cell and synaptic properties; and we record from in vivo preparations to evaluate these circuits in whole animals with the ultimate plan to develop an awake, behaving preparation to determine the relationship between behavioral and cognitive parameters and thalamocortical functioning. Stimulation techniques in slices include electrical activation and laser photostimulation involving both uncaging of glutamate (or GABA) and optogenetics; recording involves mainly patching of single neurons and imaging via flavoprotein autofluorescence. For in vivo recording, we also plan to use electrical stimulation plus optogenetics (both ChR2 to activate and NpHR to inactivate based on Cre lines to control specific pathways) with recording via electrophysiology (single cell and current source density analysis) plus imaging via flavoprotein autofluorescence or intrinsic signals. Examples of these techniques can be found among our recent publications.

 

Drivers and Modulators

We have pointed out that not all afferents to thalamic relay cells are equal, and that it is important to identify which input carries the information to be relayed. Examples of the information-bearing afferents are the retinal input to the lateral geniculate nucleus and medial lemniscal input to the ventral posterior lateral/medial nucleus. These we call the driver inputs. All other inputs to any given thalamic relay, such as those from layer 6 of cortex and the brainstem (e.g., cholinergic, noradrenergic, etc.), are modulator inputs and determine how driver inputs are relayed. Included in this modulatory role is the control of firing mode and its switching between tonic and burst plus gain control of the driver input. We have generated a list of features that distinguish drivers from modulators and have further suggested that this duality of inputs types might be applied to other pathways, such as those in cortex.

We have further developed this classification especially for glutamatergic afferents, because these are often considered to be the information bearing inputs to circuits and are generally dealt with as if they are equal participants in some sort of anatomical democracy. However, the example from thalamus makes clear that this is incorrect: the driver input (e.g., retinal) is functionally quite distinct from the layer 6 modulatory feedback, and yet both are glutamatergic. Thus many (indeed, it appears that most) glutamatergic afferents in thalamus and cortex are modulatory, much like cholinergic or noradrenergic afferents. However, there is an important distinction: these other modulatory systems tend to have poor topography and generally global effects; glutamatergic modulators are highly topographic and thus provide the sort of local modulation needed for such processes as spatial attention.

We have now extended this classification for glutamatergic inputs to cortex, and find that, based on a range of physiological and anatomical criteria, we see the same two synaptic inputs types. Because the function of each is less clear in the more complex circuitry of cortex than in thalamus, we have resorted to the neutral terminology of Class 1 and Class 2, and the former have practically identical properties to drivers in thalamus, and the latter, to modulators. Thus we hypothesize the same functions for these in cortex: Class 1 is driver and Class 2, modulator.

 

First and Higher Order Order Relays​

Because driver input determines the nature of a thalamic relay (i.e., the lateral geniculate nucleus can be characterized as a relay of retinal input), identifying the driver input to a thalamic relay is a key first step in understanding its function. In the process of doing so, we realized that the driver input to many thalamic relays originates in layer 5 of cortex. This is different from the corticothalamic pathway emanating from layer 6: all thalamic relays receive a layer 6 input, and this is largely feedback and modulatory, while only some receive an additional layer 5 input, and this is often if not exclusively feedforward and driver. Thus those with layer 5 input are the thalamic limb of a cortico-thalamo-cortical or transthalamic pathway, being a key link in a chain of corticocortical communication.

Those thalamic relays receiving driver input from the periphery or a subcortical source are first order relays, because they represent the first relay of a particular form of information (e.g., visual or somatosensory) to cortex. Those that receive a driver input from layer 5 of one cortical area and relay it to another are higher order relays, because they relay information already in cortex between areas. Examples of first order relays for vision, somesthesis, and hearing are the lateral geniculate nucleus, the ventral posterior nucleus, and the ventral part of the medial geniculate nucleus; their higher order partners are the pulvinar, posterior medial nucleus, and dorsal part of the medial geniculate nucleus. We have also identified other first and higher order relays, and it appears that most of thalamus by volume is higher order. This provides a straightforward function of relaying information between cortical areas for most of thalamus that hitherto seemed quite mysterious in terms of their roles.

This idea that higher order relays play a key role in corticocortical communication challenges the dogma that this communication is solely the result of direct corticocortical connections. A curious feature that has emerged is that often, and perhaps always, cortical areas connected directly also have a transthalamic connection organized in parallel. This raises a series of questions:


• Are direct connections always paralleled by a transthalamic one, and if not, what distinguished between these two patterns?
• What is the difference in terms of information content between the direct and transthalamic pathways?
• Why is one path relayed via thalamus?
• Are transthalamic pathways strictly feedforward in terms of cortical hierarchies or do they also contribute to feedback connections?

 

Thalamic Relays as a Corollary of Motor commands

We have noted that many and perhaps all driver inputs to thalamus, whether to first order or higher order targets, are branches of axons that also project to motor centers. Thus, for example, many or all retinal axons innervating the lateral geniculate nucleus branch to also innervate midbrain centers involved in the control of eye movements, pupil size, accommodation, etc. Furthermore, the cortical layer 5 axons innervating higher order thalamic relays branch to innervate brainstem motor regions and sometimes even the spinal cord. We thus conclude that driver inputs to thalamus play a dual role: they provide information about the rest of the body and environment and also act as efference copies of messages sent to motor centers. In this scheme, one of the roles of transthalamic circuits is to continuously upgrade these commands and simultaneously inform higher order cortical areas of messages sent to motor centers. Other possible roles are also under study.

 

Potential Clinical Correlates 

The role of higher order thalamic relays indicated above may relate to aspects of awareness of self and, along with the idea that messages relayed by these and other thalamic nuclei constitute efference copies, contribute to forward models of self and the environment. There is a long history of cognitive defects that are associated with higher order thalamic relays, and recent evidence based on MRI and postmortem anatomy in schizophrenic patients indicates that first order nuclei appear normal but higher order nuclei (e.g., the medial dorsal nucleus and pulvinar) are severely shrunken with extensive neuronal loss. Thus pathology of higher order thalamic relays may contribute to self-generated actions not being registered as such, producing inaccurate forward models. Failures in the production of normal forward models may play a significant role in producing some of the abnormal experiences encountered in schizophrenia and perhaps other cognitive disorders.

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Select Publications

Theyel, B.B., Llano, D.A., and Sherman, S.M. (2010) The corticothalamocortical circuit drives higher-order cortex. Nat. Neurosci., 13, 84-88.

Lee, C.C., and Sherman, S.M. (2010) Topography and physiology of ascending streams in the auditory tectothalamic pathway. Proc. Nat. Acad. Sci., 107, 372-377.

Llano, D.A., Theyel, B.B., Mallik, A.K., Sherman, S.M., and Issa, N.P. (2009) Rapid and sensitive mapping of long range connections in vitro using flavoprotein autofluorescence imaging combined with laser photostimulation. J.Neurophysiol., 101, 3325-3340.

Lee, C.C., and Sherman, S.M. (2008) Synaptic properties of thalamic and intracortical inputs to layer 4 of the first- and higher-order cortical areas in the auditory and somatosensory systems. J. Neurophysiol., 100, 317-326.

Sherman, S.M. (2007) The thalamus is more than just a relay, Current Opinion in Neurobiology, 17, 417-422.

Sherman, S.M , and. Guillery, R.W. (2006) Exploring the Thalamus and its Role in Cortical Function. MIT Press, Cambridge, MA.

Guillery, R.W., and Sherman, S.M. (2002) Thalamic relay functions and their role in corticocortical communication: Generalizations from the visual system, Neuron, 33, 1-20.

Viaene, A.N., Petrof, I., and Sherman, S.M. (2011) Synaptic properties of thalamic input to layers 2/3 and 4 of primary somatosensory and auditory cortices. J. Neurophysiol., 105, 278-292.

Viaene, A.N., Petrof, I., and Sherman, S.M. (2011) Synaptic properties of thalamic input to the subgranular layers of primary somatosensory and auditory cortices in the mouse. J. Neurosci., 31, 12738-12747.

Sherman, S.M. and Guillery, R.W. (2011) Distinct functions for direct and transthalamic corticocortical connections. J. Neurophysiol., 106, 1068-1077.

Viaene, A.N., Petrof, I., and Sherman, S.M. (2011) Properties of the thalamic projection from the posterior medial nucleus to primary and secondary somatosensory cortices in the mouse. Proc. Nat. Acad. Sci., 108, 18156-18161

 DePasquale, R., and Sherman, S.M. (2011) Synaptic properties of corticocortical connections between the primary and secondary visual cortical areas in the mouse. J. Neurosci., 31, 16494-16506.

Sherman, S.M. (2012) Thalamocortical interactions. Current Opinion in Neurobiology, 17, 417-422.

DePasquale, R., and Sherman, S.M. (2011) Modulatory effects of metabotropic glutamate receptors on local cortical circuits. J. Neurosci., 32, 7364-7372.

Sherman, S.M., and Guillery, R.W. (2013) Thalamocortical Processing: Understanding the Messages that Link the Cortex to the World. MIT Press, Cambridge, MA.

Sherman, S.M. (2014) The function of metabotropic glutamate receptors in thalamus and cortex. The Neuroscientist, 20: 136-149.