Circadian Clocks and Event Timers Are Localized to Different Areas of the Nervous System

The observation of circadian rhythms in unicellular organisms and the expression of circadian genes in many peripheral tissues in mammals suggest the possibility that all cells contain circadian rhythms (Balsalobre, 2002). While it is difficult to discount this possibility, expression patterns of circadian genes and brain lesion and transplant studies support specific localization of circadian clocks and event timers.

It is fairly well established in vertebrates that there is one circadian pacemaker: the suprachiasmatic nucleus (SCN) (Ralph and Hurd, 1995). The SCN is located over the optic chiasm rostral to the supraoptic nucleus. Cross-genotype transplants of SCN for Syrian hamster tau mutants have unambiguously defined the SCN as the major control mechanism of the mammalian circadian period (Ralph et al., 1990). The SCN, when moved from one hamster to another, is sufficient to alter the circadian rhythm. The SCN also shows strong expression of the mPer1 and Clock genes, which are rapidly induced there by exposure to light (Hastings, 1997; Shigeyoshi et al., 1997).

SCN neurons in hypothalamic slices are observed to fire rhythmically at around 8 to 10 Hz during the day and 2 to 4 Hz at night (Hastings, 1997; Wagner et al., 1997). Isolated SCN neurons show a spontaneous rate of firing at near the same rates as in slices (Hastings, 1997). They also show a higher-order rhythm in frequency over the circadian day. The SCN reaches most of its targets via thalamus- and hypothalamus- (e.g., the pineal gland) mediated hormonal control (Hastings, 1997).

SCN function in natural environments is still poorly understood. In the laboratory, rodents rendered arrhythmic by SCN lesions live normal life spans (DeCoursey and Krulas, 1997). Besides circadian arrhythmia, the hibernation cycle is also affected by SCN lesions. SCN-lesioned female squirrels (Spermophilus lateralis) were observed to hibernate for almost 2 years in a laboratory setting (Ruby et al., 1996). Psychophysical experiments on event timing in SCN-lesioned animals show that, despite their inability to maintain daily rhythms, they can accurately time short intervals (Mistleberger, 1993).

An ambitious study of SCN-lesioned chipmunks returned these animals to the wild after surgery. Unfortunately, after 3000 h of fieldwork over slightly more than 2 years, there was essentially no observed effect of the SCN removal (DeCoursey and Krulas, 1998). The SCN-lesioned chipmunks did show evidence of brief arrhythmia and nighttime restlessness in the wild, but the activity cycles were largely the same for all chipmunks studied. There was also no significant effect on survivability, reproduction, or winter torpor duration.

While there is no direct relationship between the SCN and event timers, event timing does have a direct relationship with the hippocampus. The hippocampus has played a starring role in mammalian learning and memory since the lesioning of the human subject H.M.'s medial temporal lobes in the 1950s. After the surgery, H.M. was completely unable to form new declarative memories (Churchland and Sejnowski, 1994). Declarative memories are akin to semantic memory in the sense that the memory is based on the learning of semantic statement. Procedural memory, for which H.M. showed only minor deficit, is based on a kind of implicit function learning. For example, H.M. was perfectly capable of learning a motor skill, but he would be unlikely to remember that he had learned it.

Since that time, a great deal of attention has been paid to the role of the hippocampus in the formation of spatial memory. In food-storing birds, damage to the hippocampus disrupts memory for storage sites (Krebs et al., 1989). As well, bird species that store food have significantly larger hippocampal formations than those that do not. The operation of the spatial function of the hippocampus appears to work via location-coding neural cells (place fields) (e.g., Mizumori et al., 1996). When the animal returns to a specific spatial location, similar cells in the hippocampus fire. This information appears to be primarily visually coded.

The function of the hippocampus has also been established in the formation of episodic memory, but not necessarily in its retrieval (Fletcher et al., 1997). Episodic memory is typically associated with the ability to recollect past events, as originally introduced by Endel Tulving (1972). It was coined to represent any type of memory that was not strictly lexical (semantic memory), and thus it would represent essentially all temporal forms of learning. Recent evidence using positron emission tomography (PET) finds the retrieval of episodic memory events localized in the right prefrontal cortex, with a limited functional role played by the hippocampus (Fletcher et al., 1997).

Hippocampal lesions are shown to operate in the formation of temporal memory in rats (Meck et al., 1984). Once the memory is formed, however, the hippocampus becomes less important. Effects of hippocampal lesions include a lack of avoidance for previously visited maze sites, the inability to withhold or inhibit previously learned response patterns, and the foreshortening of temporal memories (Kesner, 2002; Meck, 1988; Meck et al., 1984).

0 0

Post a comment