Cutler, B. | Search bioRxiv

bioRxiv2026

PGE2 modulation of stimulus valence directs zebrafish behavioral fever

Animals seek warmth during fever, but whether this behavior reflects altered temperature perception or interpretation remains unresolved. A prevailing view holds that fever reduces perceived temperature, making the environment feel colder. Here, we use behavior, modeling, and calcium imaging in larval zebrafish to test these hypotheses. We find that viral immune signals drive larval zebrafish to seek warmer temperatures in a PGE2-dependent manner. We localized PGE2 receptors to thermoregulatory brain regions that are conserved across vertebrates. Through comparative behavioral modeling we show that contrary to the prevailing view, fever does not reduce the perception of warmth. Instead, PGE2 alters the valence of temperature changes, such that heating becomes attractive while cooling turns aversive. Calcium imaging reveals that modulation of medullary activity by immune signals directs these changes in stimulus valence. Together, these results identify PGE2-driven changes in stimulus valence as a key principle of the sensorimotor basis of fever.

neuroscience↗

bioRxiv2019

Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease

Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimers disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimers disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Subjects with dementia included those with \"pure\" ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group ({beta} = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not ({beta} = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

neuroscience↗