Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 299

4.7.2 Genetic models
Clock gene expression rhythms are evident in a variety of structures impor-
tant for learning, and these local clocks may contribute to memory pro-
cesses. 354,383 The first indication that clock genes may contribute to
learning processes derived from studies demonstrating that flies with a per
null mutation displayed learning deficits in an experience-dependent court-
ship paradigm. 384 Building on this initial work, it has been demonstrated that
mice carrying a per2 null mutation display deficits in long-term potentiation
and trace fear conditioning, with normal initial acquisition and short-term
recall. 383 Similarly, per1 knockout mice display blunted hippocampal clock
gene rhythms and learning deficits in a radial armmaze task. 385 Furthermore,
mice with null mutations of either per1 or per2 display altered cocaine-
induced behavioral sensitization and place preference, with per1 mutants
and per2 mutants displaying impoverished and enhanced responses, respec-
tively. 386 However, the role of per for learning in general remains unclear, as
mice deficient for either of these genes do not display deficits in cued fear
conditioning, spatial learning in the Morris Water maze, or ethanol-induced
learning. 383,387,388 In contrast, mice lacking the clock paralog npas2 display
deficits in cued fear conditioning, but not the Morris water maze. 389 While
bmal1 mice display altered

responses under a habituation protocol, 134 these models should be studied in
the context of other learning paradigms. 390 In genetic association studies,
cognitive function following sleep deprivation has been found to be related
to a per3 polymorphisms. 391-393

/ mice, clock mutant mice, and double cry /

4.8. Immune dysfunction
Immune function and response are regulated in a circadian manner with
pronounced consequences (reviewed in Ref. 394 ). Relative to day workers,
rotating and night shift workers display a higher risk for common
infections, 395 multiple sclerosis, 396 and other autoimmune disorders. 397
Uncontrolled or chronic inflammation is a risk factor for several of the
pathologies observed under conditions of circadian disruption, such as car-
diovascular disease, 398 cancer, 399 and diabetes. 400 Thus, changes in the
immune system may represent a common factor influencing the varied
adverse health consequences associated with shift work.

4.8.1 Environmental models
In rats, chronic reversals of the LD cycle have been found to suppress
immune function, with decreased cellular

responses to concanavalin