Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission.

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Hormonal and behavioural responses of paradoxical sleep-deprived rats to the elevated plus maze.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is observed immediately after 96 h of paradoxical sleep (PS) deprivation. However, when individually or group PS-deprived rats are challenged with a mild stressor, they exhibit a facilitation of the corticosterone response, and a faster return to basal levels than control rats. Because the housing condition influences coping behaviour, we tested whether the type of PS deprivation (individually or in group) influenced anxiety-like behaviour in the elevated plus-maze and the accompanying adrenocorticotropin (ACTH) and corticosterone responses. Individually (I-DEP) or group deprived (G-DEP) rats and their appropriate control groups were either killed immediately after 96 h of sleep deprivation (time-point 0 or 'basal') or exposed to a 5-min test on the elevated plus maze and sampled 5, 20 or 60 min after test onset. Control of I-DEP rats showed reduced locomotor activity and augmented anxiety-like behaviour, replicating the effects of social isolation. Although I-DEP rats exhibited higher motor activity than cage control rats, these groups did not differ in regard to the percentage of entry and time spent in the open arms. G-DEP rats, in turn, ambulated more, entered and remained longer in the open arms, exhibiting less anxiety-like behaviour. PS-deprived rats exhibited higher ACTH and corticosterone 'basal' secretion than control rats. For all groups, peak ACTH secretion was reached at the 5-min time-point, returning to unstressed basal levels 60 min after the test, except for G-DEP rats, which showed a return at 20 min. Peak levels of corticosterone occurred at 5 min for PS-deprived groups and at 20 min for control groups. G-DEP rats showed a return to 'basal' unstressed levels at 20 min, whereas the I-DEP and control groups did so at 60 min. A negative correlation between exploration in the open arms and hormone concentrations was observed. These data indicate that housing condition influences the subsequent behaviour of PS-deprived rats in the EPM which, in turn, seems to determine the secretion profile of ACTH and corticosterone in response to the test.