Gan Lab

Understanding brain circuit dysfunction in dementia

Our brains are incredibly complex networks of cells and blood vessels working together to support our thinking, memory, and decision-making. In dementia, including Alzheimer's disease and vascular dementia, this delicate balance is disrupted, leading to cognitive decline. The Gan Lab focuses on understanding why and how brain circuits become dysfunctional in these conditions, particularly in the early stages before symptoms become apparent.

Using advanced technologies to observe and measure brain activity in living systems, the team examines key brain regions involved in memory and cognitive control. They study how changes in the interactions between brain cells, support cells, and blood vessels contribute to the development of dementia. By identifying the crucial components and connections that are affected, the Gan Lab aims to discover new targets for early intervention. This research could lead to innovative diagnostic tools to detect dementia earlier and novel therapies to halt or even reverse the progression of these devastating diseases, ultimately improving the lives of millions affected by dementia worldwide.

In vivo interrogation of synaptic and circuit dynamics underlying neurogliovascular unit impairment in dementia

The overarching aim of the Gan Lab is to understand why and how neurons and brain circuits become dysfunctional in vivo in response to alterations of neuro-vascular and neuro-glial interactions at the neurogliovascular unit (NGVU) in dementia-related disorders, such as AD and typical vascular dementia e.g. cerebral small vessel disease (cSVD). The team employs state-of-the-art in vivo electrophysiology technologies such as in vivo patch-clamp and high-density silicone probe recordings combined with quantitative behehviours in virtual reality. Complemented by cutting-edge strategies in molecular biology and in vivo imaging, we attempt to identify key molecules, cell types, and cross-brain region connectivities that may be targeted to halt or reverse the disease trajectory. 

Early NGVU alterations develop in various brain regions in dementia-related disorders, affecting typically distinct brain circuits. Firstly, the team focus on the hippocampus where NGVU dysfunction is an early marker of AD. The hippocampus is essential in the acquisition, retrieval, and consolidation of episodic memory, in particular spatial memory. Hippocampal oscillations modulate place cells in this brain region and are potentially critical in storing, packaging, and relaying spatial information. In disease conditions, mounting evidence has described alterations of oscillations in the early stages of AD, well before cognitive deficits can be diagnosed. 

Secondly, the team examine the prefrontal cortex (PFC) and related subcortical circuits. PFC has been recognised as the key brain region in exerting ‘top-down’ or executive influence on sensory, motor, and memory processing to orchestrate behaviours in accordance with goals. The PFC’s executive function is made possible because it receives from, and projects to, virtually all sensory and motor cortices and a wide range of subcortical structures. Furthermore, the PFC plays essential roles in short-term/working memory, attention, and decision-making, which are well documented in cognitive control deficits in early dementia e.g. cSVD. 

Preprint:
Action-outcome based flexible behavior requires medial prefrontal cortex lead and its enhanced functional connectivity with dorsomedial striatum, Áron Kőszeghy, Wei Xu, Mingshan Liu, Peiheng Lu, Long Wan, Peggy Series, Jian Gan bioRxiv 2023.12.12.571355; doi: https://doi.org/10.1101/2023.12.12.571355