Microglia As conTroller of braIn metaboLism During Aging

Introduction

Microglia represent the main brain residential immune cells. In the last years, evidence emerged that, besides representing the first line of defense against pathogenic insults, microglia are also centrally involved in physiological functions essential for correct CNS development and function.

Role of Microglia

Microglia, in a spatially and temporally controlled manner, influence:

• Neuronal apoptosis
• Neurogenesis
• Myelin formation
• Synapse homeostasis, including removing supernumerary synapses during development

These widely heterogeneous roles are supported by distinct subtypes—or states—of microglia, present in different regions of the brain and at different times during CNS development.

Key Gene: Trem2

In the last years, Triggering Receptor Expressed on Myeloid cells 2 (Trem2) emerged as a key gene which controls the microglial metabolic state, in addition to directing synapse elimination and shaping functional brain connectivity.

Project Proposal

In the present project, I propose that microglia, via Trem2, direct the genetic signature of specific subgroups of brain cells, shifting them toward specific metabolic and developmental patterns. I hypothesize that this mechanism is key for the control of metabolism in the hypothalamus, where the neuronal contingents orchestrating systemic energy homeostasis reside.

Methodology

By using a combination of:

1. Transcriptomics
2. Multiplex protein expression analysis
3. Cell-based imaging methods

I will determine which subsets of microglia cooperate within hypothalamic centers and will define the underlying mechanisms.

Impact of the Study

I will also assess whether defects in this orchestrated crosstalk affect the central regulation of energy and glucose homeostasis during aging. Data from this study will provide comprehensive knowledge of microglia functions in shaping hypothalamic complexity and endocrine output.

Additionally, they will offer a targeting potential for new therapeutic strategies that could reverse immunometabolic dysfunction by modulation of hypothalamic microglial function.