Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 298

profile can be ameliorated by lithium treatment or by clock rescue in the ven-
tral tegmental area. 357 Interestingly, both manic- and depressive-like behav-
iors can be induced by RNAi knockdown of clock in the ventral tegmental
area, which highlights the importance of clock gene expression within this
specific brain region for proper mood regulation. 359 Decreased depression
and anxiety are also reported in the ror knockout mouse, the per2 mutant
mice, and the fbxl3 mutant mouse, which has a 27 h period due to altered
cry degradation. 360-362 Moreover, there are a number of human genetic asso-
ciation studies that have implicated clock genes in the etiology of mood dis-
orders (reviewed in Ref. 355 ) , with most of the known clock genes
implicated ( clock , npas2 , rev - erb , ror , cry , and per ).

4.7. Learning and memory deficits
Cognitive processes in humans display circadian fluctuations and many of
the key processes involved in learning and memory display daily fluctua-
tions. 363 Environmental conditions with circadian disruption adversely
affect many of these processes. 364-368 There is also evidence for actual neu-
ropathological consequences of circadian disruption in humans, with tem-
poral lobe atrophy and spatial cognitive deficits in long-term airline flight
crews. 369,370

4.7.1 Environmental models
In humans, non-24 h LD cycles that produce misalignment between sleep:
wake cycles and melatonin secretion disrupt cognitive performance. 371 In
rodents, exposure to non-24 h LD cycles can decrease cognitive function
and produce remodeling of the prefrontal cortex. 197,372 Furthermore, sim-
ulated jetlag in rodents produces deficits in hippocampal-dependent forms of
learning and memory and reductions in hippocampal neurogenesis. 373-379
In these studies, the deficits induced by jetlag can persist after adjustment
to the shifted LD cycle and can be influenced by both procedural factors
(e.g., shift magnitude and direction) and intrinsic factors (e.g., history of
jetlag). Rats held under constant light display learning deficits associated
with altered hippocampal function. 376,380,381 Learning deficits are also evi-
dent in rodent models provided light at night under both entrained 350,352
and free-running conditions. 56 In the latter context, these light-induced
learning deficits are dependent on the presence of intrinsically photo-
sensitive melanopsin-containing retinal ganglion cells. 56 Lastly, arrhythmic
Siberian hamsters display learning deficits in a delayed novel-object

recognition task. 382