Overview
Our research focuses on the mammalian brain. Proper function of the brain relies on highly sophisticated networks composed of specialized cells, called neurons, interconnected in specific ways. We are working on two related projects to discover how these networks develop and change at the cellular and molecular levels, and how defects in these processes contribute to neurological and mental disorders.
The first project focuses on developmental remodeling of neuronal connections (synapses). Each neuron makes many synapses with other neurons early in life. Many of these early connections are later eliminated and the remaining synapses are strengthened. The process is thought to underlie important aspects of behavioral development, but little is understood about its underlying mechanisms. The second project investigates the role of serotonin in brain development. Serotonin is present in large quantities in the brains of newborns, but little is known about how it contributes to the development of neurons and synapses. We use mouse genetics and electrophysiology to investigate the mechanisms at single neuron and single synapse levels.
Research details
Brain Development and Plasticity
The mammalian brain, with billions of neurons and trillions of synapses, is by far the most complex organ of the body. The proper function of the brain relies on highly sophisticated neural networks that are composed of distinct groups of neurons interconnected in specific ways. My long-term goal is to study cellular and molecular mechanisms that are critically involved in the formation and plasticity of neural networks in the mammalian brain, and to contribute to the research on neurological and mental disorders associated with developmental defects. We currently focus on two related projects: 1) developmental remodeling of glutamatergic synapses; and 2) the role of serotonin in the maturation of neurons and synapses.
Developmental remodeling of glutamatergic synapses
Synaptic remodeling is an important process in the formation of specific neuronal connections and the development of behavior; however, little is known about the underlying mechanisms. During early development, each neuron makes connections with many target cells, but the strength of each connection is relatively weak. Many of the initial connections are later eliminated, while the remaining synapses are reinforced. This synaptic remodeling process is thought to be the neural basis of behavioral development, including the development of senses and motor skills, and speech learning. We investigate synaptic remodeling at the thalamic relay synapse of the whisker sensory system in mice as a model for studying synapse elimination and maturation in the brain.
The rodent whisker sensory system, because of its topographic organization and accessibility for sensory manipulation, has been a valuable model for studying neuronal connectivity. Tactile information from each whisker is relayed by specific groups of neurons in the brain stem and thalamus before reaching the neocortex. The primary thalamic relay synapse for the whisker system is the lemniscal synapse, where the axon of a neuron in the principal 5 nucleus (Pr5) contacts a neuron in the ventral posteromedial nucleus (VPm) in the thalamus. Previous studies have shown that in adult rats, each VPm neuron receives 1-3 lemniscal inputs from Pr5. However, it was unknown whether this specificity results from synaptic remodeling. We have recently shown that the lemniscal connection in the mouse VPm does undergo extensive synaptic remodeling during the second week after birth. Our results suggest the lemniscal synapse as a valuable model for investigating developmental remodeling at central synapses. The major goal here is to determine the underlying cellular and molecular mechanisms that control remodeling of the lemniscal synapse. Our focus is to elucidate activity-dependent mechanisms, which include the roles of various glutamate receptors and of sensory experience. We combine electrophysiology, mouse genetics, and molecular biology.
Serotonin and brain development
The vertebrate brain is extensively innervated by serotonergic (5-hydroxytryptamine; 5-HT) fibers arising from the brain stem. 5-HT axon terminals interact with other neurons in complex ways by binding of 5-HT to at least 14 distinct receptors. Consequently, 5-HT is involved in many brain functions including sleep, appetite, and cognitive function, and in numerous diseases such as obesity, epilepsy, affective illness, depression, and schizophrenia. In addition to its role in neurotransmission, 5-HT is implicated in various aspects of neural development. 5-HT is present in large quantities in the brain during early postnatal life. However, little is known about its role during this critical period of brain development.
Recent studies suggest a role for 5-HT in activity-dependent processes during development. Using patch-clamp recording in acute brain slices, we have shown that 5-HT induces strong excitatory responses in layer 5 pyramidal neurons in the prefrontal cortex during early postnatal development. Based on these observations, we propose that 5-HT promotes the maturation of neurons and synapses in the neocortex. This hypothesis will be examined using genetically modified mice in combination with quantitative electrophysiological and morphometric analyses. This study may provide new insight into the pathophysiology of autism, depression, and schizophrenia.
Lab staff
Postdoctoral Fellow: Hao Wang, Ph.D.Research Assistant I: Hong Liu, Ph.D.
Research Administrative Assistant: Patricia Cherry
Publication listings
Arsenault D, Zhang ZW. 2006. Developmental remodeling of the lemniscal synapse in the ventral basal thalamus of the mouse. J Physiol 573:121-132.
Zhang ZW. 2006. Developmental refinement in the mammalian thalamus. Crit Rev Neurobiol 18(1-2):49-59.
Zhang ZW. 2006. Postnatal development of the mammalian neocortex: Role of activity revisited. Can J Neurol Sci 33:158-169.
Timofeeva E, Dufresne C, Sik A, Zhang ZW, Deschenes M. 2005. Cholinergic modulation of vibrissal receptive fields in trigeminal nuclei. J Neurosci 25:9135-9143.
Zhang ZW, Arsenault D. 2005. Gain modulation by serotonin in layer 5 pyramidal neurons of the rat prefrontal cortex. J Physiol 566:379-394.
Zhang ZW . 2004. Maturation of layer 5 pyramidal neurons in the rat prefrontal cortex: Intrinsic properties and synaptic function. J Neurophysiol 91:1171-1182.
Zhang ZW. 2003. Serotonin induces tonic firing in layer V pyramidal neurons of rat prefrontal cortex during postnatal development. J Neurosci 23:3373-3384.
