A_central_alarm_system_that_gates_multi-sensory_innate_threat_cues_to_the_amygdala

Article Overview

• Title: A central alarm system that gates multi-sensory innate threat cues to the amygdala

• Authors: Sukjae J. Kang, Shijia Liu, Mao Ye, Dong-Il Kim, Gerald M. Pao, Bryan A. Copits, Benjamin Z. Roberts, Kuo-Fen Lee, Michael R. Bruchas, Sung Han

• Date Published: August 16, 2022

• Source: Cell Reports 40, 111222.

Key Findings

• Two populations of CGRP-expressing neurons, CGRPSPFp and CGRPPBel, are crucial for processing multi-sensory threat cues.

• These neurons relay aversive information to different subregions of the amygdala:

  • CGRPSPFp: Targets the lateral amygdala (LA).

  • CGRPPBel: Targets the central amygdala (CeA).

• Inhibition of these pathways reduces the perception of aversive stimuli and the formation of related memories.

Introduction

• Importance of Threat Perception: Perception of threats is vital for survival; animals must detect aversive information rapidly across multiple sensory modalities.

• Previous Research: Prior studies reveal that various pathways independently transmit innate threat signals to brain regions such as the midbrain and hypothalamus.

Study Aims

• To determine how multi-sensory innate threat cues are integrated and conveyed to the amygdala.

• Investigate the role of CGRP neurons in aversive learning and memory related to these cues.

Neural Circuitry

• The amygdala acts as a critical center for processing multi-sensory aversive stimuli, involved in behavioral responses and associative memory formation.

• Inputs to Amygdala: Dense presynaptic inputs to the amygdala originate from:

  • Posterior thalamus

  • Parabrachial nucleus

• CGRP Neurons: These neurons express calcitonin gene-related peptide (CGRP), linked to aversion and nociception.

Experimental Methods

• Calcium Imaging: Recorded neuronal activity while presenting mice with multi-sensory threats (e.g., foot shock, sound bursts, looming stimuli, olfactory, and gustatory cues).

• Retrograde Tracing: Identified synaptic inputs to CGRPSPFp and CGRPPBel neurons to elucidate the origin of inputs related to threat perception.

• Behavioral Analysis: Investigated freezing responses to various stimuli in silenced CGRP pathways using tetanus toxin.

Results

Activation of CGRP Neurons

• Responses to Aversive Stimuli: Most CGRPSPFp and CGRPPBel neurons increased activity in response to aversive stimuli.

  • Each neuron type responded to different sensory modalities, highlighting distinct networks activated by these threats.

Requirement for Threat Perception

• Silencing CGRP neurons led to reduced freezing behavior in response to various threats, suggesting their critical role in innate threat perception.

• Findings:

  • CGRPSPFp neurons are primarily needed for auditory and visual threat responses.

  • CGRPPBel neurons are essential for olfactory and gustatory threat responses.

Memory Formation

• Both neuronal pathways were fundamental for forming aversive memories linked to the presented stimuli.

• Mechanistic Insights: Optogenetic experiments revealed that activating these circuits resulted in freezing responses, indicating their role in fear conditioning.

Discussion

• Integrated Processing of Threat Information: The study demonstrates a shared circuitry for processing multi-sensory threat signals, enhancing survival responses.

• Clinical Implications: Understanding these pathways may provide grounds for therapeutic strategies for treating fear-related disorders, indicating the potential of targeting CGRP pathways in various psychiatric conditions.

Limitations and Future Directions

• Further investigation is required to ascertain the specific cell types within the amygdala that receive inputs from the CGRPSPFp and CGRPPBel pathways.

• Future studies may explore how different stimulus intensities impact the function of these neuronal circuits during associative memory tasks.

Acknowledgments

• The authors express their gratitude towards various funding sources and collaborators that aided in the research.