Background-Genetic markers in the serotonin transporter are associated with panic disorder. The associated polymorphisms do not include the serotonin transporter-linked polymorphic region and display no obvious functional attributes. A common polymorphism (rs3813034) occurs in one of the two reported polyadenylation signals for the serotonin transporter and is in linkage disequilibrium with the panic disorder-associated markers. If functional, rs3813034 may be the risk factor that explains the association of the serotonin transporter and panic disorder.
SUMMARY
Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females—which we leverage to illustrate the behavioral and pharmacologic relevance of these findings—and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.
BackgroundPersistently active PKMζ has been implicated in maintaining spinal nociceptive sensitization that underlies pain hypersensitivity. However, evidence for PKMζ in the maintenance of pain hypersensitivity comes exclusively from short-term studies in males using pharmacological agents of questionable selectivity. The present study examines the contribution of PKMζ to long-lasting allodynia associated with neuropathic, inflammatory, or referred visceral and muscle pain in males and females using pharmacological inhibition or genetic ablation.ResultsPharmacological inhibition or genetic ablation of PKMζ reduced mild formalin pain and slowly developing contralateral allodynia in nerve-injured rats, but not moderate formalin pain or ipsilateral allodynia in models of neuropathic and inflammatory pain. Pharmacological inhibition or genetic ablation of PKMζ also effectively reduced referred visceral and muscle pain in male, but not in female mice and rats.ConclusionWe show pharmacological inhibition and genetic ablation of PKMζ consistently attenuate long-lasting pain hypersensitivity. However, differential effects in models of referred versus inflammatory and neuropathic pain, and in males versus females, highlight the roles of afferent input-dependent masking and sex differences in the maintenance of pain hypersensitivity.
Recent advances in ultrafast electron
and X-ray diffraction have
pushed imaging of structural dynamics into the femtosecond time domain,
that is, the fundamental time scale of atomic motion. New physics
can be reached beyond the scope of traditional diffraction or reciprocal
space imaging. By exploiting the high time resolution, it has been
possible to directly observe the collapse of nearly innumerable possible
nuclear motions to a few key reaction modes that direct chemistry.
It is this reduction in dimensionality in the transition state region
that makes chemistry a transferable concept, with the same class of
reactions being applicable to synthetic strategies to nearly arbitrary
levels of complexity. The ability to image the underlying key reaction
modes has been achieved with resolution to relative changes in atomic
positions to better than 0.01 Å, that is, comparable to thermal
motions. We have effectively reached the fundamental space-time limit
with respect to the reaction energetics and imaging the acting forces.
In the process of ensemble measured structural changes, we have missed
the quantum aspects of chemistry. This perspective reviews the current
state of the art in imaging chemistry in action and poses the challenge
to access quantum information on the dynamics. There is the possibility
with the present ultrabright electron and X-ray sources, at least
in principle, to do tomographic reconstruction of quantum states in
the form of a Wigner function and density matrix for the vibrational,
rotational, and electronic degrees of freedom. Accessing this quantum
information constitutes the ultimate demand on the spatial and temporal
resolution of reciprocal space imaging of chemistry. Given the much
shorter wavelength and corresponding intrinsically higher spatial
resolution of current electron sources over X-rays, this Perspective
will focus on electrons to provide an overview of the challenge on
both the theory and the experimental fronts to extract the quantum
aspects of molecular dynamics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.