Muscarinic Acetylcholine Receptor M1’s Impact on Fear Extinction Learning

Post-Traumatic Stress Disorder (PTSD) is a mental health disorder that can occur following a traumatic event like combat, assault, or disaster. Individuals with PTSD are unable to extinguish fear memories which can become chronic and disabling. However, it remains unclear why some individuals exposed to a traumatic event develop PTSD while others are resilient. Acetylcholine plays a critical role in fear learning, but its role in fear extinction is less well understood. In this investigation, we used a rat model of fear extinction to determine if individual differences in extinction learning are correlated with markers of cholinergic signaling. Cholinergic markers included the M1 muscarinic acetylcholine receptor (M1 m-AChR) and the vesicular acetylcholine transporter (vAChT). These cholinergic markers are strongly expressed in brain regions, such as the amygdala and prefrontal cortex that contribute to the fear extinction circuit. The goal of the present study was to determine whether individual differences in cholinergic signaling in these brain regions could underlie differences in fear extinction. Expression levels of cholinergic markers were measured in amygdala and prefrontal cortex from male Long-Evans rats (N = 13) that had undergone a Pavlovian fear conditioning and extinction paradigm. We found that rats exhibited individual differences in extinction of freezing behavior following twenty presentations of a conditioned auditory stimulus. Six of 13 rats tested failed to extinguish cue-conditioned freezing behavior as defined by a median split in freezing during the last 10 tone presentations. When M1 m-AChR expression in these animals was assessed by Western blot analysis, a significant correlation was evident between expression level of M1 m-AChR in the amygdala and the freezing behavior during the extinction trials. Expression of M1 m-AChRs in amygdala of animals showing good extinction learning was significantly higher than that in animals resistant to extinction. In contrast, there was no significant correlation between vAChT expression and freezing in either amygdala or prefrontal cortex. These results suggest that low expression of M1 m-AChRs in the amygdala is correlated with deficits in fear extinction, and suggest that therapeutic strategies aimed at enhancing muscarinic signaling in amygdala may enhance fear extinction in animals and perhaps patients with PTSD

Searches for Neutrinos from Gamma-Ray Bursts Using the IceCube Neutrino Observatory

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma-rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between 2011 May and 2018 October to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to ≲1% of the observed diffuse neutrino flux, and emission on timescales up to 10$^{4}$ s is constrained to 24% of the total diffuse flux

Searches for Neutrinos from Gamma-Ray Bursts using the IceCube Neutrino Observatory

Gamma-ray bursts (GRBs) are considered as promising sources of ultra-high-energy cosmic rays (UHECRs) due to their large power output. Observing a neutrino flux from GRBs would offer evidence that GRBs are hadronic accelerators of UHECRs. Previous IceCube analyses, which primarily focused on neutrinos arriving in temporal coincidence with the prompt gamma rays, found no significant neutrino excess. The four analyses presented in this paper extend the region of interest to 14 days before and after the prompt phase, including generic extended time windows and targeted precursor searches. GRBs were selected between May 2011 and October 2018 to align with the data set of candidate muon-neutrino events observed by IceCube. No evidence of correlation between neutrino events and GRBs was found in these analyses. Limits are set to constrain the contribution of the cosmic GRB population to the diffuse astrophysical neutrino flux observed by IceCube. Prompt neutrino emission from GRBs is limited to $\lesssim$1% of the observed diffuse neutrino flux, and emission on timescales up to $10^4$ s is constrained to 24% of the total diffuse flux

Recent Progress in Solar Atmospheric Neutrino Searches with IceCube

Cosmic-rays interacting with nucleons in the solar atmosphere produce a cascade of particles that give rise to a flux of high-energy neutrinos and gamma-rays. Fermi has observed this gamma-ray flux; however, the associated neutrino flux has escaped observation. In this contribution, we put forward two strategies to detect these neutrinos, which, if seen, would push forward our understanding of the solar atmosphere and provide a new testing ground of neutrino properties. First, we will extend the previous analysis, which used high-energy through-going muon events collected in the years of maximum solar activity and yielded only flux upper limits, to include data taken during the solar minima from 2018 to 2020. Extending the analysis to the solar minima is important as the gamma-ray data collected during past solar cycles indicates a possible enhancement in the high-energy neutrino flux. Second, we will incorporate sub-TeV events and include contributions from all neutrino flavors. These will improve our analysis sensitivity since the solar atmospheric spectrum is soft and, due to oscillation, contains significant contributions of all neutrino flavors. As we will present in this contribution, these complementary strategies yield a significant improvement in sensitivity, making substantial progress towards observing this flux