Ngfr⁺ cholinergic projection from SI/nBM to mPFC selectively regulates temporal order recognition memory

Area of Science:

• Neuroscience
• Cognitive Neuroscience
• Molecular Mechanisms

Background:

• Acetylcholine is vital for cognitive functions via cholinergic pathways.
• Specific cholinergic circuits and molecular underpinnings of recognition memory are not well understood.

Purpose of the Study:

• To investigate the role of specific cholinergic subpopulations and circuits in recognition memory, particularly temporal order judgments.
• To elucidate the molecular mechanisms involving nerve growth factor receptor (NGFR) in these processes.

Main Methods:

• Utilized Ngfr knockout mice (Ngfr-/-) and selective genetic manipulations (chemogenetics, optogenetics) in ChAT-Cre mice.
• Employed fiber photometry to measure acetylcholine release in the medial prefrontal cortex (mPFC).
• Assessed temporal order memory, novel object recognition, and object location recognition.

Main Results:

• Ngfr-/- mice exhibited impaired temporal order memory but intact novel object and location recognition.
• Loss of NGFR reduced cholinergic neuron excitability in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-mPFC circuit, diminishing acetylcholine release in mPFC.
• Impaired cholinergic activity disrupted GABAergic signaling via KCC2, which was rescued by potentiating acetylcholine signaling.

Conclusions:

• The NGFR-dependent SI/nBM-mPFC cholinergic circuit is essential for temporal order recognition memory.
• NGFR signaling modulates cholinergic neuron activity, acetylcholine release, and GABAergic synaptic function, collectively underpinning recency judgments.