Microglia activation state mapping platform for immune-to-brain disease therapeutics

Overview

This research program addresses the critical role of microglia—the brain's resident immune cells—in diseases where immune system dysfunction contributes to neurological and psychiatric symptoms. The platform targets three major conditions: Parkinson's Disease, chronic inflammatory diseases causing fatigue and malaise (such as inflammatory bowel disease), and Major Depressive Disorder (MDD).

The core value proposition lies in uncovering distinct microglia activation states that emerge during these immune-to-brain neuropathologies, revealing previously unexplored therapeutic targets. By understanding how microglia interact with neurons and lymphocytes in both disease progression and healthy affective regulation, this work opens new avenues for treating conditions where current therapies are limited.

Technical specifications

Novel in vivo disease models:

• Two proprietary models for early-stage Parkinson's Disease featuring human α-Synuclein overexpression in the substantia nigra, producing motor deficits and microglia activation before neuronal death occurs
• A Gq-DREADDs microglia activation model enabling controlled study of microglial contributions to disease progression
• Two models for healthy affective regulation following inflammatory challenge, including LPS-induced sickness behavior and an MDD fecal microbiota transplantation (FMT) model

Validation findings to date:

• Five weeks post-injection: increased microglia numbers and size without neuronal loss, accompanied by motor dysfunction (Rotarod, Pole test, amphetamine-induced locomotion, grooming) but unchanged affective state
• Single-cell sequencing reveals previously uncharacterized lymphocyte involvement and novel microglia signaling pathways
• 24 hours post-LPS challenge: acute sickness transitions to a positive affective state with increased hedonic responding

Planned analytical pipeline:

• CellChat software for analyzing microglia-neuron-lymphocyte signaling from RNAseq data
• In vivo FDG-PET imaging combined with ex vivo iDISCO whole-brain clearing and IBA1+ and c-fos+ cell staining
• SlideSeq spatial transcriptomics from 10x Genomics for characterizing affective microglia-neuron hubs
• Behavioral validation in depression mouse models

Technology readiness level

The platform is at an early-to-mid research stage (TRL 3-4). The disease models have been established and initial behavioral and single-cell sequencing validation has been completed in mice (n=10-16 per experimental group). Key molecular targets have been identified through preliminary sequencing work but require further validation. The research team is actively seeking collaboration to advance target identification, validate therapeutic candidates in behavioral models, and explore translational potential for treating immune-to-brain diseases. The work represents fundamental discovery research with clear pathways toward therapeutic application.