Advances in the Neurobiology of Mental Illness

The difficulty of obtaining brain tissue from living human patients has stumped progress towards understanding the cellular and molecular mechanisms underlying complex psychiatric disorders. However, in recent years, development of induced pluripotent stem cells (iPSC), and further differentiation into different brain cell types and cerebral organoids, have attempted to overcome this limitation and are at the fore-front of psychiatric research.  Cells in these cultures demonstrate similar characteristics to cells found in vivo, in regards to gene transcription and cellular processes, and the potential of these constructs as probes in studies of psychiatric disorders has only recently begun to be exploited. Dr. Walss-Bass will discuss some of these patient brain-derived mechanistic studies carried out in her laboratory, including schizophrenia studies using multiplex families and a novel model using brain cells and neurons derived from postmortem fibroblasts to examine brain cell signaling and gene networks in addiction.

Psychiatric disorders involving psychosis are typically associated with hallucinations and delusions. However, hedonic and motivational impairments are a frequent additional component of psychotic disorders that causes significant disability and functional impairment. Unfortunately, current treatments do little to improve such impairments in psychosis, in part due to a lack of understanding of the mechanisms that lead to such deficits. This talk will overview a program of research focused on understanding the neural and psychological processes that may be contributing to such motivational impairments in psychosis. Our work suggests that such impairments do not reflect deficits in immediate hedonic experience or responses to incentives, or alterations in putatively striatally mediated prediction errors as reflected in either computational analyses of either behavior of functional imaging data. However, our data suggest that such motivational impairments may reflect challenges in the representation and maintenance of incentive information that should normally serve to drive behavior, processes that are supported in part by neural circuits involving dorsal frontal/parietal and cingulo-opercular networks. Further, such motivational impairments in psychosis may also reflect impairments in the computations associated with cognitive and physical effort allocation, which relate to hedonic and goal directed behavior in every day life.

In this lecture, Dr. Stevens will discuss recent work that implicates brain immune cells, called microglia, in sculpting of synaptic connections during development and their relevance to autism, schizophrenia and other brain disorders.

Her recent work revealed a key role for microglia and a group of immune related molecules called complement in normal developmental synaptic pruning, a normal process required to establish precise brain wiring. Emerging evidence suggests aberrant regulation of this pruning pathway may contribute to synaptic and cognitive dysfunction in a host of brain disorders, including schizophrenia. Recent research has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in complement C4, gene plays a well-known role in the immune system but also helps sculpt developing synapses in the mouse visual system (Sekar et al., 2016). Together these findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. Stevens will discuss this and ongoing work to understand the mechanisms by which complement and microglia prune specific synapses in the brain. A deeper understanding of how these immune mechanisms mediate synaptic pruning may provide novel insight into how to protect synapses in autism and other brain disorders, including Alzheimer’s and Huntington’s Disease.