Corticolimbic activation patterns during aversive audiogenic stress assessed by cerebral perfusion using [^99mTc]HMPAO...

Emotional experiences modulate behavior by influencing the central and peripheral nervous systems, playing a crucial role in the pathophysiology of neuropsychiatric disorders. This study investigates the neural mechanisms underlying anxiety-like responses induced by an aversive acoustic stimulus in Wistar rats. Using [^99mTc]HMPAO single photon emission computed tomography / computed tomography (SPECT/CT) imaging, we assessed regional cerebral blood flow (rCBF) changes and correlated them with behavioral responses.

Male rats were subjected to either an unpredictable acoustic stressor or control conditions in an open field paradigm (OFP). Behavioral assessments included freezing, grooming, rearing, and escape responses, with blood samples collected to measure change in corticosterone levels. SPECT/CT imaging was performed after both stimulation and retention sessions to analyze changes in rCBF.

Our results demonstrate significant increased brain activity of the ventral hippocampus, amygdala, periaqueductal gray, hypothalamus and entorhinal/perirhinal areas with engagement of retrosplenial, frontal association and auditory cortices during the presentation of the acoustic aversive stimulus. Additionally, decreased brain activity of the orbitofrontal cortex, ventral striatum, basal forebrain and motor/somatosensory and cerebellar clusters are also observed, all consistent with a rapidly assembled defensive state integrated across the uptake window. Behaviorally, stressed animals exhibited escape responses as well as increased freezing and reduced grooming and exploratory rearing during exposure, indicating heightened anxiety. Upon context re-exposure, we observed lower activation patterns in retrosplenial cortex and dorsal hippocampus and higher activity in cingulate and orbitofrontal cortices, with small right-lateral amygdala/bed nucleus of stria terminalis clusters. Zona incerta, hypothalamus, piriform cortex and basal forebrain showed relative increased activation, while periaqueductal gray and inferior colliculus activation were reduced, indicating early-stage monitoring and vigilance with limited context-map engagement, rather than robust context fear retrieval. Corticosterone levels rose from pre- to post-session in both groups without intergroup differences.

Time-anchored perfusion SPECT delineates a threat-responsive mesocorticolimbic-midbrain circuitry during unexpected acoustic stress, prominently implicating the ventral hippocampus, and reveals a shift at context re-entry toward prefrontal monitoring with attenuated hippocampal/retrosplenial and midbrain defensive signals. These findings contribute to understanding the neural substrates of anxiety disorders, with implications for developing targeted interventions.