Tristan Shuman, Ph.D. - US grants

Project Summary/Abstract Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive impairments. Memory impairments in AD increase with age and are linked to hyperexcitability, interneuron death, circuit remodeling, and impaired interneuron function. Interneuron loss and dysfunction are well established in AD, yet it remains unclear how these anatomical changes contribute to cognitive deficits. Interneurons play a critical role in synchronizing local networks to generate brain rhythms important for long- term potentiation and memory encoding and interneuron loss has been associated with reduced oscillations and memory impairments in AD models. Understanding how hippocampal interneurons are functionally altered in AD, both before and after the emergence of learning impairments, is critical to understanding these cognitive deficits. In this proposal, we will test the hypothesis that hippocampal interneuron synchrony is altered in AD model mice, and that network dysfunction in young, pre-symptomatic mice can predict memory impairments. To examine the relationship between interneuron activity and local networks, we will use silicon probes to record simultaneously from local field potentials and single units throughout CA1 and dentate gyrus (DG) of 3xTg-AD and wild type mice running in virtual reality. We will first examine the firing patterns of interneurons in 6 month old AD model mice, after the onset of memory impairments. We hypothesize that interneurons in AD model mice will have abnormal firing patterns relative to network oscillations, which will desynchronize interneurons across CA1 and DG. Next, we will use young 3xTg-AD mice, prior to memory impairments, in order to investigate whether specific network changes can predict future cognitive decline. We hypothesize that alterations in network function (such as interneuron phase locking, oscillation power or coherence) will predict the severity of memory impairments at a later time point. These experiments will highlight potential targets for early therapeutic interventions and lead to new insights into the progression of memory impairments in AD. Characterizing hippocampal desynchrony in AD and how it contributes to cognitive deficits will be critical in developing targeted treatments for AD, especially preventative intervention during the pre-symptomatic phase where success is most viable.

Project Summary Pathological substance use disorders are a public health crisis leading to tremendous morbidity and mortality for afflicted patients and incalculable costs to society at large. Addiction to cocaine and other psychostimulants accounts for a significant proportion of this burden of disease, and treatment of these patients is currently limited by the lack of any FDA-approved pharmacotherapies. Despite significant advances in our understanding of the dopaminergic, glutamatergic, and intracellular signaling cascades altered in models of stimulant use disorders, efforts to develop medications aimed at treating stimulant use disorder have been unsuccessful. There is a growing appreciation for the role of neuroimmune interactions in normal brain function and plasticity as well as in the pathophysiology of neuropsychiatric diseases. Microglia, the resident immune cells of the CNS, interact with neurons, prune synapses, and produce neurotrophic factors that can alter synaptic plasticity and behavior. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a cytokine that is increased in blood and brain following prolonged cocaine. Systemic injections of G-CSF enhance the formation of conditioned place preference and enhance motivation to self-administer cocaine. Additionally, G-CSF potentiates cocaine induction of the immediate early gene c-Fos and enhances dopamine release from the ventral tegmental area into the nucleus accumbens (NAc). Interestingly, the receptor for G- CSF is expressed exclusively on microglia in the NAc. In this proposal we will utilize cutting-edge in vivo imaging technology to directly visualize and interrogate the effects of this microglial modulator on patterns of neuronal activity that encode cocaine administration and seeking. In Aim 1 we will record calcium signals in D1 and D2 expressing medium spiny neurons in the NAc of animals treated with G-CSF or vehicle during active cocaine self-administration or during a drug seeking task. Given that the D1 and D2 expressing populations of neurons have been shown to have opposing effects on encoding rewarding stimuli, these experiments will provide crucial information as to how G-CSF is shifting the balance of patterns of neural activity between these two discrete cell populations. In Aim 2, we will test the causal nature of G-CSF signaling through microglia by using a transgenic mouse model that deletes the G-CSF receptor exclusively in microglia and measure behavioral and neural circuit changes. Together, these experiments will characterize the neural circuit changes induced by G-CSF signaling through microglia and elucidate the mechanisms by which microglial signaling controls cocaine-associated behavior.

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found major deficits in learning and memory as well as in the precision and stability of CA1 place cells. However, it remains unclear whether impaired spatial coding in CA1 is primarily due to local processing deficits in hippocampus or rather is influenced by impaired spatial coding and synchronization from upstream inputs. In fact, there is significant evidence that upstream inputs into the hippocampus from the medial entorhinal cortex (MEC) may be altered in epilepsy. This proposal will test the hypothesis that both MEC inputs into the hippocampus have altered spatial coding and synchronization. To test this hypothesis, we will first use calcium imaging with miniature microscopes to characterize how chronic epilepsy alters spatial coding in MECII stellate cells and MECIII neurons, which directly input into hippocampus. Next, we will use silicon probes to record single unit firing and LFPs simultaneously in MECII, MECIII, DG, and CA1 and determine how synchronization throughout the entorhinal-hippocampal circuit is altered in epileptic mice. Finally, we will use excitatory and inhibitory DREADDs to modulate MEC neurons in control and epileptic mice and determine how each input into hippocampus alters synchronization of hippocampal circuits and spatial memory. Together, these aims will use state-of-the-art recording and manipulation techniques to determine precisely where and how spatial coding and synchronization breaks down in epileptic mice and gain new insights into the cause of cognitive deficits.