USING MOUSE GENETICS TO DECODE OUR SENSE OF TOUCH
Every time we step out into the world a multitude of stimuli are stamped onto the circuits of our brain by way of our sensory systems. There's a lot that we don't yet understand about all of our five senses, but touch remains particularly under-explored. However, touch is one of the first senses to develop in utero and the only sense that if deprived of during early childhood can result in catastrophic consequences to our brain and body function. Our group utilizes the power of mouse molecular genetics to identify and manipulate the circuits of touch to begin to unravel this vital yet obscure sense and its contribution to health and disease.
Innocuous touch of the skin is detected by distinct populations of sensory neurons, the Low-Threshold Mechanoreceptors (LTMRs). Our genetic labeling and visualization of LTMR subtypes revealed a remarkable organization of peripheral endings surrounding each of the three major hair follicles types in mouse. This intricate peripheral innervation pattern supports an integrative model whereby the complex mechanical properties of tactile stimuli engage hair follicle subtypes and thus differential activate unique combination of LTMRs.
The spinal cord dorsal horn decodes the unique ensemble activities of LTMR subtypes. A major obstacle to progress in innocuous touch circuit dissection is the difficulty in recognizing distinct populations of interneurons and projection neurons within the spinal cord that receive and process LTMR information, the LTMR-Recipient Zone (LTMR-RZ). To address this issue, we have identified genetic markers and developed fluorescent reporter as well as recombinase mouse genetic tools for 11 distinct interneuron populations representing ~80% of the LTMR-RZ. Each interneuron population segregates into previously uncharacterized classes of excitatory and inhibitory locally projecting interneurons, with unique morphological/physiological signatures, connectivity profiles, and contributions to tactile-based behaviors. |
Ongoing work in the lab tackles the following questions:
What is the functional organization within the spinal cord that give rise specific behavioral features?
How are these circuits affected after spinal cord injury?
Our work has shown that inactivating two distinct lineages within the LTMR-RZ gives rise to partially overlapping and distinct deficits in behavioral features related to touch, pain and/or locomotion. This work suggests that within the spinal cord dorsal horn there are unique circuit modules that underlie particular behaviors. Current work combines intersectional mouse genetics with various behavioral assays (including assays using machine learning paradigms) to uncover this modular organization. Recovery after spinal cord injury is greatly improved with touch based therapies, however it is unclear the neurons and circuits responsible for this recovery. Insights learned by our intersectional mouse genetic strategies are being applied to mouse spinal cord injury models to shed light on the neurons and circuits behind this functional recovery.
How do supraspinal centers - including the cortex and brainstem - modulate somatosensory processing in the spinal cord dorsal horn?
We know that our experience of touch is conditioned by context. This is because the brain does not simply encode sensory information, but it integrates it with with contextual information such as reward, expectation, attention, and motor action. Our work has shown that the LTMR-RZ receives direct descending cortical input. This input population represents 40% of all vGluT1+ puncta into the dorsal horn and has the capacity to modulate all interneuron subtypes within the LTMR-RZ. In collaboration with the Margolis lab here at Rutgers (http://margolislab.cbn.rutgers.edu/) we are trying to uncover when these descending networks engage touch circuits in the spinal cord and how they may modulate touch perception during behavior.
How does touch shape our social brain?
Aside from its discriminative function, touch provides another important submodality that is key to our humanity; the affective modality. Embedded in our social network, culture, and even in our every-day language, touch stands out as a critical sense for social interaction and how we define ourselves as human beings. Terms like: let's keep in touch, stroke of genius, finishing touch, etc, all point to the evolution of touch in social cultures as more than just another sensation. Further, depriving humans of touch early in development results in devastating consequences to formation of a healthy brain. Mice, like humans, also depend on touch for normal development and the formation of their own intricate social structure. Current efforts utilize the power of mouse molecular genetics to define the cells, molecules and pathways of the spinal cord affective touch circuit and understand its contribution to development and social interaction.
What is the functional organization within the spinal cord that give rise specific behavioral features?
How are these circuits affected after spinal cord injury?
Our work has shown that inactivating two distinct lineages within the LTMR-RZ gives rise to partially overlapping and distinct deficits in behavioral features related to touch, pain and/or locomotion. This work suggests that within the spinal cord dorsal horn there are unique circuit modules that underlie particular behaviors. Current work combines intersectional mouse genetics with various behavioral assays (including assays using machine learning paradigms) to uncover this modular organization. Recovery after spinal cord injury is greatly improved with touch based therapies, however it is unclear the neurons and circuits responsible for this recovery. Insights learned by our intersectional mouse genetic strategies are being applied to mouse spinal cord injury models to shed light on the neurons and circuits behind this functional recovery.
How do supraspinal centers - including the cortex and brainstem - modulate somatosensory processing in the spinal cord dorsal horn?
We know that our experience of touch is conditioned by context. This is because the brain does not simply encode sensory information, but it integrates it with with contextual information such as reward, expectation, attention, and motor action. Our work has shown that the LTMR-RZ receives direct descending cortical input. This input population represents 40% of all vGluT1+ puncta into the dorsal horn and has the capacity to modulate all interneuron subtypes within the LTMR-RZ. In collaboration with the Margolis lab here at Rutgers (http://margolislab.cbn.rutgers.edu/) we are trying to uncover when these descending networks engage touch circuits in the spinal cord and how they may modulate touch perception during behavior.
How does touch shape our social brain?
Aside from its discriminative function, touch provides another important submodality that is key to our humanity; the affective modality. Embedded in our social network, culture, and even in our every-day language, touch stands out as a critical sense for social interaction and how we define ourselves as human beings. Terms like: let's keep in touch, stroke of genius, finishing touch, etc, all point to the evolution of touch in social cultures as more than just another sensation. Further, depriving humans of touch early in development results in devastating consequences to formation of a healthy brain. Mice, like humans, also depend on touch for normal development and the formation of their own intricate social structure. Current efforts utilize the power of mouse molecular genetics to define the cells, molecules and pathways of the spinal cord affective touch circuit and understand its contribution to development and social interaction.