|Crandall SR, Patrick SL, Cruikshank SJ, Connors BW Infrabarrels Are Layer 6 Circuit Modules in the Barrel Cortex that Link Long-Range Inputs and Outputs.. Cell Reports. 2017; 21 (11) : 3065-3078.|
|Crandall SR, Cruikshank SJ, Connors BW A Corticothalamic Switch: Controlling the Thalamus with Dynamic Synapses.. Neuron. 2015; 86 (3) : 768-82.|
|Cruikshank SJ, Ahmed OJ, Stevens TR, Patrick SL, Gonzalez AN, Elmaleh M, Connors BW Thalamic control of layer 1 circuits in prefrontal cortex.. Journal of Neuroscience. 2012; 32 (49) : 17813-23.|
|Lee SC, Cruikshank SJ, Connors BW Electrical and chemical synapses between relay neurons in developing thalamus.. The Journal of Physiology. 2010; 588 (Pt 13) : 2403-15.|
|Cruikshank SJ, Urabe H, Nurmikko AV, Connors BW Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons.. Neuron. 2010; 65 (2) : 230-45.|
|Parker PR, Cruikshank SJ, Connors BW Stability of electrical coupling despite massive developmental changes of intrinsic neuronal physiology.. Journal of Neuroscience. 2009; 29 (31) : 9761-70.|
|Cruikshank SJ, Connors BW Neuroscience: State-sanctioned synchrony.. J. Geophys. Res.. 2008; 454 (7206) : 839-40.|
|Connors BW, Cruikshank SJ Bypassing interneurons: inhibition in neocortex.. Nature Neuroscience. 2007; 10 (7) : 808-10.|
|Cruikshank SJ, Lewis TJ, Connors BW Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex.. Nature Neuroscience. 2007; 10 (4) : 462-8.|
|Long MA, Cruikshank SJ, Jutras MJ, Connors BW Abrupt maturation of a spike-synchronizing mechanism in neocortex.. Journal of Neuroscience. 2005; 25 (32) : 7309-16.|
|Cruikshank SJ, Landisman CE, Mancilla JG, Connors BW Connexon connexions in the thalamocortical system.. Progress in brain research. 2005; 149 : 41-57.|
|Cruikshank SJ, Hopperstad M, Younger M, Connors BW, Spray DC, Srinivas M Potent block of Cx36 and Cx50 gap junction channels by mefloquine.. Proceedings of the National Academy of Sciences. 2004; 101 (33) : 12364-9.|
|Cruikshank SJ, Rose HJ, Metherate R Auditory thalamocortical synaptic transmission in vitro.. Journal of Neurophysiology. 2002; 87 (1) : 361-84.|
|Cruikshank SJ, Weinberger NM In vivo Hebbian and basal forebrain stimulation treatment in morphologically identified auditory cortical cells.. Brain Research. 2001; 891 (1-2) : 78-93.|
|Cruikshank SJ, Killackey HP, Metherate R Parvalbumin and calbindin are differentially distributed within primary and secondary subregions of the mouse auditory forebrain.. Neuroscience. 2001; 105 (3) : 553-69.|
|Hsieh CY, Cruikshank SJ, Metherate R Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist.. Brain Research. 2000; 880 (1-2) : 51-64.|
|Metherate R, Cruikshank SJ Thalamocortical inputs trigger a propagating envelope of gamma-band activity in auditory cortex in vitro.. Exp Brain Res. 1999; 126 (2) : 160-74.|
|Cruikshank SJ, Weinberger NM Evidence for the Hebbian hypothesis in experience-dependent physiological plasticity of neocortex: a critical review.. Brain research. Brain research reviews. 1996; 22 (3) : 191-228.|
|Cruikshank SJ, Weinberger NM Receptive-field plasticity in the adult auditory cortex induced by Hebbian covariance.. Journal of Neuroscience. 1996; 16 (2) : 861-75.|
|Cruikshank SJ, Edeline JM, Weinberger NM Stimulation at a site of auditory-somatosensory convergence in the medial geniculate nucleus is an effective unconditioned stimulus for fear conditioning.. Behavioral Neuroscience. 1992; 106 (3) : 471-83.|
My research is directed at understanding processing mechanisms in thalamus and neocortex. Techniques include in vitro and in vivo intracellular and extracellular electrophysiology, pharmacology, central microstimulation, anatomy, behavior and optogenetics. The goal has been to characterize the organization and operation of thalamo-cortical circuits and to contribute to the understanding of information processing in the forebrain.
AUDITORY FOREBRAIN PLASTICITY IN VIVO:
My graduate work involved the in vivo study of synaptic plasticity in auditory forebrain, focusing on contributions of Hebbian induction mechanisms to receptive field changes during behavioral learning (Cruikshank & Weinberger, J Neurosci, 1996). I also examined interactions between plasticity and arousal state, including the role of the basal forebrain cholinergic system (Cruikshank & Weinberger, Br Res, 2001). Techniques included behavioral (Cruikshank et al, Behav Neurosci, 1992) and neurophysiological methods, involving cell-attached recordings with patch electrodes in vivo, at times from awake guinea pigs.
AUDITORY THALAMOCORTICAL ORGANIZATION AND FUNCTION:
My intial postdoctoral studies focused on the organization and function of the auditory forebrain (Cruikshank, et. al, Neuroscience, 2001). I helped develop an in vitro auditory thalamocortical slice preparation and used it to examine anatomy, physiology and pharmacology of connections within the system (Metherate & Cruikshank, EBR, 1999; Cruikshank et al, J Neurophysiol, 2002). One major finding was that acetylcholine agonists suppress cortical synaptic responses originating from intracortical sources more strongly than those from thalamic sources (Hsieh, Cruikshank & Metherate, Br Res, 2000). This suggests that during periods of high acetylcholine release, such as behavioral arousal, acetylcholine tips the balance in cortex, selectively suppressing ongoing intracortical activity, thus favoring external sensory information.
THALAMOCORTICAL MICROCIRCUITRY AND OPTOGENETICS:
As a research professor at Brown University I have worked on three main topics:
1. ELECTRICAL SYNAPSES: There are two basic modes of synaptic communication: chemical and electrical. Until recently, most neuroscientists assumed that electrical synapses were limited to a few brainstem areas. This assumption was shattered in 1999 with the discovery of widespread electrical connections between neocortical inhibitory cells (Galaretta & Hestrin, Nature, 1999; Gibson et al., Nature, 1999). One of my goals at Brown has been to help understand electrical synapse function in thalamus and cortex (Cruikshank et. al, Prog Br Res, 2005). A fundamental part of this has been to characterize the spatial and temporal distributions of gap junctions. For example, we discovered electrical coupling between thalamic relay cells (Lee, Cruikshank & Connors, J Physiol, 2010), contradicting an emerging consensus that electrical synapses were exclusively located among inhibitory cells of forebrain. We have also investigated the developmental time course of coupling and the gap junction proteins involved, utilizing connexin knockout mice. We found dramatic differences in the developmental expression patterns for two highly interconnected thalamic nuclei. Relay cells of the ventrobasal thalamus undergo a precipitous decline in coupling during the first two postnatal weeks (Lee, Cruikshank & Connors, J Physiol, 2010) whereas inhibitory cells of the thalamic reticular nucleus maintain stable coupling across the same period despite massive developmental changes in intrinsic cellular properties (Parker, Cruikshank & Connors, J Neurosci, 2009). The pharmacology of electrical synapses is another basic research contribution. While most blockers of gap junctions have poor specificity, we recently characterized a compound called mefloquine, which we found to be a potent and relatively specific blocker of the neuronal connexin (Cx36)(Cruikshank et al, PNAS, 2004). Partly due to our study, mefloquine has become a widely used tool in gap junction research. Finally, I have also contributed to more direct studies of electrical synapse function. For example, we found that gap junction-mediated synchrony of neocortical interneurons can synaptically synchronize surrounding excitatory cells (Long, Cruikshank, Jutras & Connors, J Neurosci, 2005). However, we lack a clear understanding of gap junction function in thalamocortical processing (Cruikshank et al., Prog Br Res, 2005) so this remains an important subject for future research.
2. MECHANISMS OF THALAMOCORTICAL PROCESSING. The second topic I have pursued at Brown is cortical processing of thalamic input, beginning with the earliest stages: mono- and disynaptic thalamocortical responses in cortical layer 4 (Cruikshank et al, Nature Neurosci, 2007). My focus has been on interactions between excitatory spiny stellate and inhibitory fast spiking (FS) interneurons, both of which receive monosynaptic thalamic projections and connect to one another. Thalamocortical responses are much stronger in FS interneurons than in excitatory cells. I found that this response difference is due to synaptic (rather than intrinsic) mechanisms; thalamocortical input onto FS interneurons is stronger and faster than that onto excitatory cells, partly due to a greater thalamic innervation. These strong and fast inputs cause FS cells to spike. FS firing, in turn, produces short latency inhibition on surrounding excitatory neurons, suppressing their responses. Interestingly, the FS cells also synapse on other FS cells. However, because thalamocortical synapses onto FS cells have extremely fast kinetics, they are able to fire action potentials before significant feedforward inhibition has time to emerge (Cruikshank et al, Nature Neurosci, 2007). These discoveries have led to a variety of important issues/questions which provide a basis for much of my current research.
3. CORTICAL AND THALAMIC INTERACTIONS STUDIED WITH CHANNELRHODOPSINS. The third main area I have pursued at Brown is the application of optogenetic technology to understanding thalamocortical microcircuitry. Our group was among the earliest in this effort. One area of major progress has been the use of channelrhodopsins in long range stimulation/mapping experiments. Channelrodopsins are light-sensitive membrane cation channels that allow for neural activation when illuminated with blue light. These channels can be densely expressed in axons and terminal arbors of neurons (not just their soma or dendrites) and these axons/arbors can be excited by light even when severed from parent cell bodies. This feature is highly useful for studying long distance synaptic pathways for which it is difficult or impossible to make brain slices with intact connections between areas of interest.
We initially leveraged this to compare sensory thalamocortical and corticothalamic processing, revealing contrasting principles of feedforward inhibition in the two pathways (Cruikshank et al, Neuron, 2010). More recently we applied this technique to other projection systems, including non-sensory thalamocortical (Cruikshank et al, J Neurosci, 2012) and intrathalamic systems (Martinez-Garcia et al, SFN 2016, 2018). Perhaps most importantly, the method was key to unraveling how top-down corticothalamic (CT) projections from layer 6 systematically regulate thalamus in a frequency-dependent and bidirectional manner (Crandall, Cruikshank & Connors, Neuron, 2015; Crandall et al, Cell Rep, 2017). This finding has provided an inroad to much of our ongoing work.
- NIH R01NS100016, 7/17-6/22 “Neocortical control of the thalamus” Role = PI (a dual-PI grant with Barry Connors as second PI).
- NSF 1738633, 9/17 to 9/19 “Acquiring and propagating expertise in closed-loop precision optical control of neuronal activity using spatial light modulation (SLM) combined with multiphoton imaging” Role = PI.
- NIH R01NS050434-06, 2/14-1/18 (currently in NCE), “Functions of electrical synapses in inhibitory networks” Role = Co-Investigator; Barry Connors is PI.
- NIH P20GM103645 COBRE Center Pilot Project, 9/16-9/17 “Neocortical Control of the Thalamus” Role = PI
- Brown OVPR Grant Resubmission Award, 8/16 to 8/17, “Neocortical control of the thalamus” Role = PI (a dual-PI submission with Barry Connors as second PI). This award provided support to improve an R01 proposal for re-submission to NIH. We used it successfully, receiving a fundable score.
|Berson, David||Sidney A. Fox and Dorothea Doctors Fox Professor of Ophthalmology and Visual Science, Chair of Neuroscience|
|Connors, Barry||L. Herbert Ballou University Professor of Neuroscience|
|Moore, Christopher||Associate Director of the Carney Institute of Brain Science, Professor of Neuroscience|
I have participated in two types of teaching. The first is through lectures and laboratory courses on various neuroscience topics (listed below). The second is as one-on-one advisor to undergraduate and graduate students within the reasearch laboratories that I have been part of over more than 25 years. I've supervised optogenetic, physiological, anatomical and behavioral neuroscience research in the laboratories of N. Weinberger at UC Irvine (1989-1997), R. Metherate at UC Irvine (1997-2001) and B. Connors at Brown University (2001-present). The students that I've advised at Brown Unverisity are presented below the course list
Secondary laboratory advisor to four graduate students at Brown University (their official primary advisor was Barry Connors, Department of Neuroscience):
Supervisor to five undergraduates in the laboratory of Barry Connors, Brown University department of Neuroscience, advising on independent study and honors research:
Research supervisor to six undergraduate students at UC Irvine (1990-2001)