We hypothesize that normal aging triggers a homeostatic increase in GABA_A receptor α2 subunit expression within central amygdala CRF neurons, which counteracts their intrinsic hyperexcitability and preserves low anxiety despite declining amygdala‑prefrontal connectivity. This compensatory mechanism depends on preserved GABAergic interneuron function and is overridden when systemic inflammation elevates IL‑1β, which suppresses α2 transcription via NF‑κB signaling, unmasking CRF‑driven fear extinction deficits and producing treatment‑resistant anxiety in older adults.

Key predictions:

1. Aged mice (24‑month) will show higher α2 subunit mRNA and protein in CeA‑CRF neurons compared with young adults, while total GAD67‑positive interneuron numbers remain unchanged.
2. Chemogenetic activation of CRF neurons in aged mice will produce less fear‑potentiated startle and faster extinction than in young mice, an effect reversed by α2‑subunit‑specific antagonist (e.g., L‑655,708).
3. Peripheral LPS challenge (0.5 mg/kg i.p.) in aged mice will reduce CeA‑CRF α2 expression within 6 h, increase CRF neuron firing (measured by in vivo electrophysiology), and impair fear extinction; these changes will be prevented by pretreatment with an IL‑1 receptor antagonist (anakinra).
4. In aged mice with a history of early‑life pain (plantar incision at P7), the α2 compensatory rise will be blunted, and LPS will produce a larger extinction deficit than in aged controls, modeling the interaction of early stress and inflammaging.

Experimental approach:

• Use CRF‑IRES‑Cre mice crossed with a floxed‑α2‑subunit reporter to quantify subunit levels via RNAscope and immunofluorescence in CeA subnuclei.
• Perform extracellular recordings from identified CRF neurons before and after LPS or anakinra.
• Assess fear extinction using a standard tone‑shock paradigm; measure freezing across trials and retention at 24 h.
• Pharmacologically block α2 receptors with L‑655,708 (0.5 mg/kg i.p.) to test necessity of the compensatory tone.
• Include groups: young (3 mo), aged (24 mo), aged+early‑life pain, each with saline, LPS, LPS+anakinra, and LPS+antagonir treatments.

If the hypothesis holds, we will observe: (a) elevated α2 in aged CRF neurons correlating with low baseline anxiety; (b) loss of this elevation after inflammatory challenge, predicting heightened anxiety and extinction failure; (c) a synergistic deficit when early‑life stress precedes aging, explaining why a subset of older adults develops late‑life generalized anxiety disorder despite normative age‑related anxiety decline. This model directly tests whether aging engages a GABA‑mediated brake on CRF hyperactivity that can be overwhelmed by inflammaging, offering a mechanistic bridge between circuit‑level observations and clinical phenotypes of anxiety in the elderly.