Our lab focuses on studying neuroinflammation and understanding the mechanisms involved in inflammatory responses within the brain. We study the role of neuroinflammation in the context of different disease states, insults, and stressors. Understanding the context, course and duration of the neuroinflammatory response is vital to understanding the corresponding behavioral and biochemical consequences. Additionally, neuroinflammation plays a central role in the underlying pathophysiology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease as well as various substance use disorders such as alcohol use disorder and stimulant use disorder. Thus, the aim of our laboratory is to understand the role of neuroinflammation in the pathophysiology of several classes of disorders listed below and study the role of novel, anti-inflammatory compounds as potential therapeutic interventions for these conditions. 

The image on the left depicts  Glial fibrillary acidic protein (GFAP) staining for astrocytes as a marker of astrogliosis in the rat hippocampus.

Approximately 20 million adults in the United States suffer from alcohol use disorder (AUD)
Current treatments for AUD include naltrexone, disulfuram, and acomprosate. However, a high percentage of AUD patients remain refractory to such therapy. Thus, we are studying neuropharmacological and neurobiological systems that mediate alcohol abuse and dependence, with an emphasis on brain serotonin systems and neuroinflammation to potentially develop new therapeutics for AUD.  We specifically use techniques and measures such as the two bottle-choice ethanol drinking paradigm, ethanol-induced conditioned place preference (CPP) and ethanol-induced loss of righting reflex (LORR) assay.  We use these assays to evaluate the potency and efficacy of several anti-inflammatory compounds such as the phytochemical beta-caryophyllene (BCP), its derivative  oxide (BCPO) and the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI)  for AUD. 

The graph on the left depicts data from mice drinking either  ethanol or water using the two bottle-choice ethanol drinking paradigm

Our lab is involved in assessing the persistent behavioral and neurochemical effects of exposure to various classes of stimulants such as methamphetamine, MDMA and synthetic cathinones such α-pyrrolidinopropiophenone (α-PPP). Additionally, we also aim to identify novel drug targets to prevent the devastating adverse events associated with stimulant overdose.  Thus, current research in our laboratory involves characterizing the neurotoxic effects of stimulant overdose such as stimulant-induced lethality, hyperthermia, convulsions, seizures and monoamine neurochemistry depletion. Additionally, we also study various agents like HT2A receptor antagonist M100907 ,the sigma 1 (σ1) receptor antagonist BD 1047 and other anti-inflammatory compounds and peptides to attenuate adverse effects of stimulant overdose using techniques such as behavioral pharmacology,surgical telemetric probe implantation, electroencephalography and neurochemistry analysis by High Performance Liquid Chromatography (HPLC). 

TThe image on the left depicts representative electroencephalography waveforms over a period of 60 s following administration of 78 mg/kg of methamphetamine (or baseline). Data showing the effects of pretreatment with vehicle, M100907 (1 mg/kg), BD 1047 (10 mg/kg), and the combination of M100907/BD 1047 (1/10 mg/kg) on seizures are shown.

Alzheimer's disease (AD) is responsible for major financial and health-care burdens to society. It is estimated that the costs are likely to grow as our population ages further. Current therapeutics for AD only provide transient symptom management and do not alter the course of the disease. Interestingly, AD affects a greater proportion of females as compared to males. A leading hypothesis for the pathology of AD involves the production of toxic forms of Amyloid-beta plaques and neurofibrillary tangles in the brain which trigger inflammation-mediated neurotoxicity. The cholinergic system is most widely studied for AD related pathophysiology. However, more recent studies also implicate other neurotransmitter systems such as serotonin and norepinephrine which play vital roles in modulating behaviors such as fear and anxiety.  Thus, our research focuses on studying different neurotransmitter systems implicated in AD and characterizing sex differences and epigenetic alterations in AD. Additionally we are also investigating the  role of novel anti-inflammatory agents as potential therapeutics for AD using techniques such as behavioral pharmacology, autoradiography, proteomics, immunohistochemistry and neurochemical analysis. 

The image on the left shows App knock-in mice from our breeding colony that were specifically engineered by researchers at the Riken Brain Science Institute in Japan to display AD-like pathology.

The blood-brain barrier (BBB) limits the therapeutic use of large molecules and peptides as it prevents them from passively entering the brain following administration by conventional routes. We use nanotechnology drug delivery systems for encapsulating peptides such as Oxytocin and Neuropeptide Y to increase their brain bioavailability through active transport and increase their duration of action through encapsulation and sustained release. Preclinical and clinical studies suggest pro-social behavioral effects of these peptides and therapeutic promise. Thus, we specifically evaluate the therapeutic effects and increased bioavailability of these formulations for conditions such as alcohol use disorder (AUD) , Substance use disorder and opioid use disorder using in vitro  techniques such as cell-culture model of the BBB, and in vivo techniques such as bioimaging, cerebrospinal fluid analysis, behavioral testing and EEG (electroencephalography).

The image on the left shows brain uptake in mice at 30 minutes (above) or 4 hours (below) of an encapsulated large-molecule dye in a nanoformulation (left and middle). The red uptake in the Tf-NP nanoparticles shows that our technology has actively transported this dye into the brain successfully.

Parkinson’s Disease (PD) is amongst the most common neurodegenerative diseases. It is clinically manifested by motor symptoms including resting tremors, postural instability, rigidity, and bradykinesia. The neuropathogenesis of PD symptomology is directly linked to the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SN), where cell death leads to subsequent depletion of the key neurotransmitter dopamine (DA). Polyunsaturated fatty acids (PUFA), including the family of omega-3 fatty acids (w3FA) that contains a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have a long record of linkage to brain function. Thus, our research focuses on studying the neuroprotective and dopamine synthesizing effects of omega-3 fatty acids for PD and investigating the potential mechanisms through which they act using behavioral, molecular and neurochemical techniques.   

 

The image above shows a UHPLC coupled to electrochemical detectors (ECD) used to quantify tissue levels of neurotansmitters such as Dopamine and its primary metabolite DOPAC. 

Additional research focus areas of the laboratory include:

• Studying the effects of a high fat diet on monoamine neurochemistry
• Comparing the psychoactive effects of various psychedelics such as 2,5-Dimethoxy-4-iodoamphetamine (DOI) and other tryptamines
• Investigating the anxiolytic and sedative properties of various naturally occurring sesquiterpenes
• Using optogenetics as a tool to investigate into mechanisms associated with anxiety with the ultimate aim to develop therapeutic interventions for anxiety related disorders