Veronique VanderHorst Laboratory
Research in the VanderHorst Laboratory
About the PI
Early in her career Veronique VanderHorst, MD, PhD, trained in systems brainstem and spinal neuroanatomy at the Univ of Groningen in the Netherlands (Gert Holstege), at the Univ of California at San Francisco (Peter Ralston), the Primate Center at the Univ of Wisconsin, Madison (Ei Terasawa) and at Karolinska Institute in Stockholm, Sweden (Brun Ulfhake).
Her earlier work involved the organization of motoneurons in the lumbosacral spinal cord, descending motor pathways involved in vocalization and reproduction, as well as ascending spinal-midbrain systems. She studied estrogen-induced plasticity in these pathways at the light- and electron microscopic level, looked at gender differences in these neural circuitries, and mapped estrogen receptors in neurochemically different brainstem and spinal cell groups. Her expertise spans a variety of species, from mouse to non-human primates.
She moved on to train in clinical neurology at the BIDMC. She sub-specialized in movement disorders (Daniel Tarsy), and is now on staff.
In her current research projects she takes full advantage of her expertise in brainstem and spinal neuroanatomy, and applies this to clinically relevant questions related to movement disorders.
Neural circuitries important for gait, posture and tone
The overall goal of our studies is to understand gait (walking) disorders caused by problems in the central nervous system. Gait disorders are very common and often lead to falls and decreased mobility, which affect quality of life and increase morbidity and mortality. Problems in the central nervous system that cause gait problems include neurodegenerative diseases such as Parkinson's disease, loss of neural connections due to strokes, trauma (spinal cord injury) or demyelinating disease, and aging.
When the nervous system is intact, walking feels automatic and simple. However, when gait problems develop it becomes obvious that walking is a highly complex function. It can decompensate in many ways, from problems with initiation (freezing of gait), to changes in speed (bradykinetic or the opposite, festinating gait) and stride length. Often gait disorders are accompanied by problems with balance, posture, coordination, strength or somatosensory feedback.
The neural circuitries mediating normal gait are poorly understood, and we do not understand how dysfunction of these circuitries leads to various gait or other movement abnormalities. By making detailed measurements of temporal and spatial parameters of gait and other motor functions under normal conditions and following modulation of distinct clusters of neurons in the central nervous system, we will learn which circuitries are important and how these circuitries function together. The results of our studies will provide insights that help to develop more powerful, targeted strategies to manage gait problems.
Mouse and human models
We use a variety of transgenic mouse models to anatomically and functionally identify circuitries in the brainstem and spinal cord that control 1) initiation of movement, 2) rhythm, 3) stance and swing duration and stride length as a function of speed, 4) tone, 5) recruitment, and 6) posture.
In addition, as a first step to assess to what extent our findings are relevant for human disease conditions, we aim to correlate pathological changes in homologous regions of the human post mortem brainstem and spinal cord with ante-mortem gait and other motor abnormalities. This project is conducted in close collaboration with Dr David Bennett and Dr Aron Buchman at Rush University in Chicago (Religious Order Study and the Memory and Aging Project).
In our current studies we focus on the medial medullary reticular formation, a region of loosely assembled neurons in the lower part of the brainstem, which is well preserved among species from rodents to non-human primates and humans.
This region receives converging information from many areas involved in motor control. Neurons in this region in turn project heavily to the spinal cord, directly or indirectly innervating motoneurons, the neurons that control our muscles. As such, this region is well positioned to play a key role in the control of gait.
Though we know from prior research studies that this region is important for locomotion in animal species, we know little about the organization and function of subpopulations of neurons in this region mainly because available methods did not allow to separate out these partially overlapping populations in intact models.
In our projects we take advantage of state of the art and innovative approaches which allow us to dissect the organization and function of different types of excitatory and inhibitory neurons in this region, as well as their afferent and efferent mono- and multisynaptic connections with relevant regions in the forebrain, midbrain/pons and spinal cord.
To better understand the anatomical and functional organization of neurons within the medial medulla, to unravel its ascending and descending projections, and to study the role of these distinct pathways in the control of movement, we use a variety of anatomical, physiologic and molecular techniques. These include: a) conventional and conditional (Cre recombinase dependent) anterograde and retrograde tracers to visualize pathways of interest, b) selective and focal deletion of excitatory or inhibitory signaling mediated by a variety of vesicular transporters, c) focal, viral vector mediated cre-dependent expression of designer receptors (so called DREADDs) which allows for reversible and selective activation or inhibition of our pathways of interest (in collaboration with Dr Brad Lowell, BIDMC), d) in vitro electrophysiology (in collaboration with Dr Elda Arrigoni, BIDMC).
The effects of selective, acute or chronic inactivation or activation of distinct groups of neurons on gait and other motor functions are then measured using a battery of behavioral and electrophysiological tests, including high speed video gait analysis (free walk and treadmill) and kinematic measurements, tests of complex motor functions such as beam, ladder, open field, and rotarod, and chronic electromyography recordings (EMG) to quantify activation patterns of subsets of muscles during different activities (in collaboration with Karim Fouad, Univ Alberta, Canada; Nancy Chamberlin, BIDMC). We also measure the effects of our interventions on muscle tone during REM sleep. This is relevant for REM sleep behavior disorder, which is common in patients with Parkinson's disease (in collaboration with Clif Saper, BIDMC).
Using immunohistochemistry and in situ hybridization, we can then very precisely identify the neurons that were affected by our interventions and reconstruct the circuitries in which they take part. This includes visualization of midbrain and forebrain regions that are connected with distinct cell populations in the medial medulla, and characterization of the subclasses of interneurons and motoneurons in the spinal cord that receive input from these distinct cell groups.
Figure Legends (top to bottom)
Cre dependent expression of mCherry (red) in neurons expressing mRNA of the vesicular GABA transporter (yellow).
Schematic representation of the position of the joints of the hindlimb and pelvis of a mouse during the swing phase (normal condition).
Top: Reticulospinal neurons that express mRNA for the vesicular GABA or glutamate transporter 2 (in red and blue). Bottom: Photomicrographs showing anterogradely labeled fibers in spinal cord that are derived from neurochemically distinct populations of medullo-spinal neurons (unrelated to the neurons depicted on the top).
Alpha-synuclein immunoractive Lewy bodies (brown) in the human brainstem.
Raw EMG signals of the gastrocnemius muscle during walking (left) and swimming (right).
Stance duration (top) and swing duration (bottom) plotted against velocity, before (black) and after (red) an experimental intervention in mice.