Light deprivation damages neurons and causes depression

Experiments from Gonzalez and Aston-Jones on how light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats:

Light is an important environmental factor for regulation of mood. There is a high frequency of seasonal affective disorder in high latitudes where light exposure is limited, and bright light therapy is a successful antidepressant treatment. We recently showed that rats kept for 6 weeks in constant darkness (DD) have anatomical and behavioral features similar to depressed patients, including dysregulation of circadian sleep–waking rhythms and impairment of the noradrenergic (NA)-locus coeruleus (LC) system. Here, we analyzed the cell viability of neural systems related to the pathophysiology of depression after DD, including NA-LC, serotoninergic-raphe nuclei and dopaminergic-ventral tegmental area neurons, and evaluated the depressive behavioral profile of light-deprived rats. We found increased apoptosis in the three aminergic systems analyzed when compared with animals maintained for 6 weeks in 12:12 light-dark conditions. The most apoptosis was observed in NA-LC neurons, associated with a significant decrease in the number of cortical NA boutons. Behaviorally, DD induced a depression-like condition as measured by increased immobility in a forced swim test (FST). DD did not appear to be stressful (no effect on adrenal or body weights) but may have sensitized responses to subsequent stressors (increased fecal number during the FST). We also found that the antidepressant desipramine decreases these neural and behavioral effects of light deprivation. These findings indicate that DD induces neural damage in monoamine brain systems and this damage is associated with a depressive behavioral phenotype. Our results suggest a mechanism whereby prolonged limited light intensity could negatively impact mood.

Stronger or weaker brain synapses after sleep?

Why do we spend a third of our lives asleep? The answers suggested so far are varied and controversial. It is well documented that improvement in learning and memory accompanies a night of sleep. One idea is that most new information is discarded during sleep, as diurnal animals are bombarded by stimuli during the day, most of which we want to (or need to) forget. Synapses need to recover. If this is the dominant reason why we sleep, then decreased numbers of synapses or synapse weakening should be a prominent neuronal feature of sleep. Fountain points to an article by Tonini and colleagues (Nature Neuroscience 11, pp. 200 - 208, 2008) that provides evidence for this option. Tononi suggests that after sleep "“we get a leaner brain — there’s a gain in terms of energy, space and supplies, and you are ready to learn anew.” Here is their abstract:

Plastic changes occurring during wakefulness aid in the acquisition and consolidation of memories. For some memories, further consolidation requires sleep, but whether plastic processes during wakefulness and sleep differ is unclear. We show that, in rat cortex and hippocampus, GluR1-containing AMPA receptor (AMPAR) levels are high during wakefulness and low during sleep, and changes in the phosphorylation states of AMPARs, CamKII and GSK3beta are consistent with synaptic potentiation during wakefulness and depression during sleep. Furthermore, slope and amplitude of cortical evoked responses increase after wakefulness, decrease after sleep and correlate with changes in slow-wave activity, a marker of sleep pressure. Changes in molecular and electrophysiological indicators of synaptic strength are largely independent of the time of day. Finally, cortical long-term potentiation can be easily induced after sleep, but not after wakefulness. Thus, wakefulness appears to be associated with net synaptic potentiation, whereas sleep may favor global synaptic depression, thereby preserving an overall balance of synaptic strength.

Seasonal Affective Disorder - an evolutionary relic?

Friedman offers a succinct summary of information of seasonal affective disorder (SAD), with some interesting facts.

Epidemiological studies estimate that its prevalence in the adult population ranges from 1.4 percent (Florida) to 9.7 percent (New Hampshire).

In one study, patients with SAD

...had a longer duration of nocturnal melatonin secretion in the winter than in the summer, just as with other mammals with seasonal behavior.Why did the normal patients show no seasonal change in melatonin secretion? One possibility is exposure to industrial light, which can suppress melatonin.
...The effects of light therapy are fast, usually four to seven days, compared with antidepressants, which can take four to six weeks to work.
...People are most responsive to light therapy early in the morning, just when melatonin secretion begins to wane, about eight to nine hours after the nighttime surge begins...How can the average person figure that out without a blood test? By a simple questionnaire that assesses “morningness” or “eveningness” and that strongly correlates with plasma melatonin levels. The nonprofit Center for Environmental Therapeutics has a questionnaire on its Web site (www.cet.org).

Memories play back on fast forward during sleep

It is know that correlations of nerve activity that are observed during learning sequence tasks replay during sleep, presumably to enhance learning and retention of the sequence. (I always find that I can play a difficult piano passage better when I wake up in the morning than when I was practicing it the day before). McNaughton and his collaborators now show that the replay during sleep occurs much faster than during actual awake behaviors. Here is their abstract:

As previously shown in the hippocampus and other brain areas, patterns of firing-rate correlations between neurons in the rat medial prefrontal cortex during a repetitive sequence task were preserved during subsequent sleep, suggesting that waking patterns are reactivated. We found that, during sleep, reactivation of spatiotemporal patterns was coherent across the network and compressed in time by a factor of 6 to 7. Thus, when behavioral constraints are removed, the brain's intrinsic processing speed may be much faster than it is in real time. Given recent evidence implicating the medial prefrontal cortex in retrieval of long-term memories, the observed replay may play a role in the process of memory consolidation.

Sleep deprivation diminishes recall of neutral and positive, but not of negative, events.

We remember emotional events, particularly negative ones, better than neutral events. Sterpenich et al. show that while consolidation of neutral and posititive memories is diminished by sleep deprivation, recall of negative events is less compromised. They show that after sleep deprivation, recollection of negative, potentially dangerous, memories recruits an alternate amygdalo-cortical network, which would keep track of emotional information despite sleep deprivation. Here is their description of the work:

Declarative memories, which can be consciously and verbally retrieved, are initially critically dependent on the hippocampus. However, reliable retrieval of long-term memory depends on a process of consolidation, which partly occurs during sleep, when memories are thought to be progressively transferred to long-term cortical stores. Because people tend to remember emotional memories better than neutral ones, we wondered whether the emotional significance of a memory would enhance its consolidation in a sleep-dependent manner. During a first session, participants viewed pictures with neutral and emotional content without realizing that their memory of the pictures and their content would be tested later (called incidental encoding). Three days later, during a functional MRI scanning session, subjects indicated whether they recognized previously viewed and new pictures. Half of the subjects were totally sleep deprived during the first post-encoding night, but all subjects slept as usual during the second and third post-encoding nights. We show here that the recollection of emotional stimuli elicited larger responses in the hippocampus and various cortical areas in the well-rested group than in the sleep-deprived group, suggesting that emotional significance boosts memory consolidation of the information during sleep. Interestingly, in sleep-deprived subjects, recollection of negative items recruited another network including the amygdala, as if an alternate consolidation process allowed them to keep track of negative, potentially dangerous, information despite the cognitive aftermath of sleep deprivation.

Lucid Dreaming makes the Styles section...

My, my, my..... how rapidly esoteric mind things become trendy. The lead article of the Sunday Styles section of the Sept 16 NY Times featured lucid dreaming. I've been to several consciousness meeting in which whole sessions were devoted to this capability. Actually it is not that esoteric...you probably have had experiences of being aware you were dreaming, of watching the action as a observer. The capability can be trained, and one can sometimes direct the action (even to the extent of indulging in some sexual fantasies that may not exactly be playing out in real life). I have played with this capability in my own dreaming, and find it to be much easier and cheaper than getting into computer facilitated alternative realities such as Second Life (I tried that too, felt like a dunce, and can't imagine how anyone finds the time.....).

Fly brains/Human brains - similarities in sleep induction

Some membrane signaling pathways important in initiating sleep appeared in a common ancestor of humans and insects! Here is the abstract from Foltenyi et al. (the pathways are complicated, but you can get the over all idea):

Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated [ed. note - these are proteases] activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals.

And a graphic from the review by Colwell:

Proposed role of extracellular signal–regulated kinase (ERK) in the regulation of sleep in Drosophila.
(a) Rho-mediated activation of ERK signaling increases sleep duration. During the night, Rho activation in the pars intercerebralis (PI) leads to the production and secretion of an EGFR ligand. The resulting phosphorylation of EGFR activates ERK in the tritocerebrum (TriC). Although the final targets of this signaling pathway are not known, the phosphorylated ERK seems to stay in the processes of the TriC neurons and may well regulate electrical activity and synaptic transmission in these neurons. (b) During wakefulness, Rho signaling in the PI is proposed to be downregulated, resulting in basal levels of ERK signaling. Inhibition of Rho expression in PI neurons results in decreased sleep levels, with short, fragmented sleep bouts. This observation suggests that these mutant flies have an increased need for sleep but are unable to stay asleep (making them a fly model of insomnia).

Threads of our lives in dreams...

Rebecca Cathcart writes an article on dreaming and "big dreams" (PDF here) that resonates with my own experience of having, particularly before waking, emotionally intense dreams whose story line seems to be an obvious attempt to integrate important personal issues. Some clips:

Big dreams are once again on the minds of psychologists as part of a larger trend toward studying dreams as meaningful representations of our concerns and emotions...The dreaming imagination does not just harvest images from remembered experience...It has a “poetic creativity” that connects the dots and “deforms the given,” turning scattered memories and emotions into vivid, experiential vignettes that can help us to reflect on our lives....Cultural narratives in regions like Vietnam and North and South America assign special importance to such dreams and consider them actual encounters with the spirits of lost loved ones...This notion is so widely shared by traditions all across the globe that some scholars have gone so far as to argue that religion itself actually originated in dream experience.

The article emphasizes the role of dreams in dealing with death and grief.

Grief itself is transformative. It is a process of disassembly. The bereaved must let go of the selves they were, as well as the loved ones they have lost. The dreams we have while grieving are an important part of that process...Our dreams have to do with how we internalize the people we love...You learn to look within for the loved one and the particular function that person played in your life, such as caretaking or guidance in the case of a parent. This becomes part of a function that you can provide for yourself.

Dreams that occur during rapid eye movement, or REM, cycles are the most memorable and emotionally powerful...The dreams have power because brain activity during REM is most similar to that of a waking state. The emotional responses to REM dream content, therefore, are most like the responses during waking cognition...Core body temperature rises gradually from its nadir in the middle of the night during slow-wave sleep, the least active brain state. As morning nears, subcortical brain activity tied to the circadian cycle increases. When these cycles coincide in the last and longest REM phase... the mind produces its most dramatic dreams...the four or five phases of REM in a normal night’s sleep might include similar dream content. Just as the image of a lost loved one stimulates parts of the brain associated with loss, the content of dreams early in the sleep cycle could set the tone for that night’s dream experiences. Our memories upon waking, therefore, may be our recollection of a night’s cumulative dream content.

Yawn to cool your brain?

A curious and slightly flakey bit: Eric Nagourney in Tuesday's Science section of the NY Times describes work by Gallup et al (PDF here) published in the Journal Evolutionary Psychology. It seems to me they might have actually measured brain temperature instead of just speculating about it. Nagourney notes the proposal by Gallup et al. that:

yawning... is a way for the body to cool the brain...volunteers yawned more often in situations in which their brains were likely to be warmer...To prove their theory that yawning regulates brain temperature when other systems in the body are not doing enough, the researchers took advantage of the well-established tendency of people to yawn when those around them do — the so-called contagious yawn...The volunteers were asked to step into a room by themselves and watch a video showing people behaving neutrally, laughing or yawning. Observers watching through a one-way mirror counted how many times the volunteers yawned...Some volunteers were asked to breathe only through their noses as they watched. Later, volunteers were asked to press warm or cold packs on their foreheads...“The two conditions thought to promote brain cooling (nasal breathing and forehead cooling) practically eliminated contagious yawning,” the researchers wrote.

The study may also help explain why yawning spreads from person to person...A cooler brain, Dr. Gallup said, is a clearer brain...So yawning actually appears to be a way to stay more alert. And contagious yawning, he said, may have evolved to help groups remain vigilant against danger.

Use Viagra to recover from jet lag?

I always perk up when I see reports of new side effects of sildenafil (Viagra), because it is an inhibitor of one form of an enzyme, cyclic GMP phosphodiesterase, that my earlier research showed to be central to changing light into a nerve signal in the rod and cone cells of our retinas (check here if you are curious about this previous life..). One of the interesting side effects of viagra is on color vision. Here is another interesting bit from Agostino et al. in PNAS:

Mammalian circadian rhythms are generated by a master clock located in the suprachiasmatic nuclei and entrained by light-activated signaling pathways. In hamsters, the mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase, cGMP and its related kinase (PKG). It is not completely known whether interference with this pathway affects entrainment of the clock, including adaptation to changing light schedules. Here we report that cGMP-specific phosphodiesterase 5 is present in the hamster suprachiasmatic nuclei, and administration of the inhibitor sildenafil (3.5 mg/kg, i.p.) enhances circadian responses to light and decreases the amount of time necessary for reentrainment after phase advances of the light–dark cycle. These results suggest that sildenafil may be useful for treatment of circadian adaptation to environmental changes, including transmeridian eastbound flight schedules.

A magnet for your sleep?

Massimini et al. show that the deep sleep important in brain restoration and memory consolidation (associated with EEG slow-wave activity of 0.5–4.5 Hz) can be triggered and deepened by appropriate transcranial magnetic stimulation at less than 1 Hz. (PDF here.) How long will it be before we are being offered electromagnetic "sleep caps" to improve our memory and brain restoration during sleep?
Here is their abstract:

During much of sleep, cortical neurons undergo near-synchronous slow oscillation cycles in membrane potential, which give rise to the largest spontaneous waves observed in the normal electroencephalogram (EEG). Slow oscillations underlie characteristic features of the sleep EEG, such as slow waves and spindles. Here we show that, in sleeping subjects, slow waves and spindles can be triggered noninvasively and reliably by transcranial magnetic stimulation (TMS). With appropriate stimulation parameters, each TMS pulse at less than 1 Hz evokes an individual, high-amplitude slow wave that originates under the coil and spreads over the cortex. TMS triggering of slow waves reveals intrinsic bistability in thalamocortical networks during non-rapid eye movement sleep. Moreover, evoked slow waves lead to a deepening of sleep and to an increase in EEG slow-wave activity (0.5–4.5 Hz), which is thought to play a role in brain restoration and memory consolidation.

Just a nap will do it.....

It doesn't take overnight, Nishida and Walker show that just taking a nap boosts memory consolidation.

Two groups of subjects trained on a motor-skill task using their left hand – a paradigm known to result in overnight plastic changes in the contralateral, right motor cortex. Both groups trained in the morning and were tested 8 hr later, with one group obtaining a 60–90 minute intervening midday nap, while the other group remained awake. At testing, subjects that did not nap showed no significant performance improvement, yet those that did nap expressed a highly significant consolidation enhancement. Within the nap group, the amount of offline improvement showed a significant correlation with the global measure of stage-2 NREM sleep. However, topographical sleep spindle analysis revealed more precise correlations. Specifically, when spindle activity at the central electrode of the non-learning hemisphere (left) was subtracted from that in the learning hemisphere (right), representing the homeostatic difference following learning, strong positive relationships with offline memory improvement emerged–correlations that were not evident for either hemisphere alone.

(Note: sleep spindles are a defining electrophysiological signature of NREM sleep involving short (~1 ) synchronous burst of activity (12–15 Hz) that may represent triggers of synaptic potentiation leading to neural plasticity.)

Legend (click to enlarge figure): Spindle density and offline (nap) memory enhancement. a, Correlations between offline motor memory enhancement and spindle density in the non-learning hemisphere (electrode site C3) and learning hemisphere (electrode site C4) individually. b, Correlations between offline motor memory improvement and the subtracted difference in spindle density between the learning hemisphere versus the non-learning hemisphere (C4–C3).

Robot Dreams

There is a very interesting exchange in the Letter section of the March 2 issue of Science Magazine. R. Conduit comments on a perspectives article "What do robots dream of?" (17 Nov. 2006, p. 1093) by C. Adami, which provides an interesting interpretation of the Report "Resilient machines through continuous self-modeling" by J. Bongard et al. (17 Nov. 2006, p. 1118).

Bongard et al. designed a robot with an algorithm of its stored sensory data to indirectly infer its physical structure. The robot was able to generate forward motion more adaptively by manipulating its gait to compensate for simulated injuries. Adami equates this algorithm to "dreams" of prior actions and asks whether such modeling could extend to environmental mapping algorithms. If this were possible, then a robot could explore a landscape until it is challenged by an obstacle; overnight, it could replay its actions against its model of the environment and generate (or synthesize) new actions to overcome the obstacle (i.e., "dream up" alternative strategies). It could then return the next day with a new approach to the obstacle......

This work in robotics complements current findings regarding sleep and dreaming in humans. There is now strong evidence in human sleep research showing that performance on motor and visual tasks is strongly dependent on sleep, with improvements consistently greater when sleep occurs between test and retest. This is generally believed to be related to neural recoding processes that are possibly connected to dreaming during sleep). However, when one considers human dreaming, it is not a simple replay of daily scenarios. It has complex, distorted images from a vast variety of times and places in our memory, arranged in a random, bizarre fashion. If we are to model such activity in robots, we would need to have some form of "sleep" algorithm that randomizes memory and combines it in unique arrays. This could be a way to generate unique approaches to scenarios that could be simulated. Otherwise, how else would scenario replay be an improvement over repeated trials in the environment?when one considers human dreaming, it is not a simple replay of daily scenarios. It has complex, distorted images from a vast variety of times and places in our memory, arranged in a random, bizarre fashion. If we are to model such activity in robots, we would need to have some form of "sleep" algorithm that randomizes memory and combines it in unique arrays. This could be a way to generate unique approaches to scenarios that could be simulated. Otherwise, how else would scenario replay be an improvement over repeated trials in the environment?

After a further comment letter from C. Adami, Lipson, Zykov and Bongard (the original authors) comment:

The analogy between machine and human cognition may suggest that reported bizarre, random dreams may not be entirely random. The robot we described did not just replay its experiences to build consistent internal self-models and then "dream up" an action based on those models. Instead, it synthesized new brief actions that deliberately caused its competing internal models to disagree in their predictions, thus challenging them to falsify less plausible theories and, as a result, improving its overall knowledge of self. It is possible that the mangled experiences that people report as bizarre dreams correspond to this unconscious search for actions able to clarify their self-perceptions. Many of the intermediate candidate models and actions developed by the robot (as seen in Movie S1 in our Supporting Online Material) were indeed very contorted, but were optimized nonetheless to elucidate uncertainties. Edelman (1), Calvin (2), and others have suggested the existence of competitive processes in the brain. Perhaps the fact that human dreams appear mangled and brief is exactly because they are--as in the robot--"optimized" to challenge and improve these competing internal models?

Indeed, analogies between machines learning from past experiences and human dreaming are potentially very fruitful and may be applicable in both directions. Although robots and their onboard algorithms are clearly simpler and may bear little or no direct relation to humans and their minds, it may be much easier to test hypotheses about humans in robots. Conversely, ideas from human cognition research may help direct robotic research beyond merely serving as inspiration. Specifically, it is likely that as robots become more complex and their internal models are formed indirectly rather than being explicitly engineered and represented, indirect probing techniques developed for studying humans may become essential for analyzing machines too.

Losing a night's sleep makes you less able to form new memories.

Yoo et al. report that :

..a single night of sleep deprivation produces a significant deficit in hippocampal activity during episodic memory encoding, resulting in worse subsequent retention. Furthermore, these hippocampal impairments instantiate a different pattern of functional connectivity in basic alertness networks of the brainstem and thalamus. We also find that unique prefrontal regions predict the success of encoding for sleep-deprived individuals relative to those who have slept normally. These results demonstrate that an absence of prior sleep substantially compromises the neural and behavioral capacity for committing new experiences to memory. It therefore appears that sleep before learning is critical in preparing the human brain for next-day memory formation—a worrying finding considering society's increasing erosion of sleep time.

During sleep: a brain memory dialogue

It has been known for some time that specific patterns of nerve firing in "place cells" of the rat hippocampus occur during learning a visual maze and that these patterns are replayed during sleep, apparently as a part of memory consolidation. Wilson's laboratory at M.I.T. (reporting in Nature Neuroscience) have now studied multicell spiking patterns in both the visual cortex and hippocampus during slow-wave sleep in rats. As Nicholas Wade notes in the NYTimes, the recordings capture dialogue between the hippocampus, where initial memories of the day's events are formed, and the neocortex, the sheet of neurons on the outer surface of the brain that mediates conscious thought and contains long-term memories.

Ji and Wilson found that spiking patterns not only in the visual cortex but also in the hippocampus were organized into frames, defined as periods of stepwise increase in neuronal population activity. The multicell firing sequences evoked by awake experience were replayed during these frames in both regions. Furthermore, replay events in the sensory cortex and hippocampus were coordinated to reflect the same experience. These results imply simultaneous reactivation of coherent memory traces in the cortex and hippocampus during sleep that may contribute to or reflect the result of the memory consolidation process. Because the fast rewinds in the neocortex tended to occur fractionally sooner than their counterparts in the hippocampus, Wilson thinks the dialogue is probably being initiated by the neocortex, and reflects a querying of the hippocampus's raw memory data.

Wade's review quotes comments from Wilson:
“The neocortex is essentially asking the hippocampus to replay events that contain a certain image, place or sound...The neocortex is trying to make sense of what is going on in the hippocampus and to build models of the world, to understand how and why things happen...These models are presumably used to direct behavior...They are able to generate expectations about the world and plausibly fill in blanks in memory.

Though the neocortex learns from the hippocampus, the raw memory traces, from childhood onward, are not transferred and are probably retained in the hippocampus... If so, the forgetfulness of age would arise because of problems in accessing the hippocampus, not because the data has vanished.

The subject matter of the neocortex-hippocampus dialogue in rats seems mostly to concern recent events. This is consistent with what people report when awoken from nondreaming sleep — usually small snatches of information about recent events. Dr. Wilson also said that the new findings, by showing activity in the visual neocortex, confirmed that rats had humanlike dreams with visual imagery, a possibility some researchers had doubted."

Sleep deprivation slows the generation of new nerve cells

An interesting finding from Mirescu et al.... It is known that prolonged sleep deprivation is stressful, has adverse effects on cognitive performance and health, and raises corticosterone levels. Their work looks at new nerve cell formation (neurogenesis) in the rat hippocampus, which is central to cognitive performance. They show "that sleep deprivation inhibits adult neurogenesis at a time when circulating levels of corticosterone are elevated. Moreover, clamping levels of this hormone prevents the sleep deprivation-induced reduction of cell proliferation. The recovery of normal levels of adult neurogenesis after chronic sleep deprivation occurs over a 2-wk period and involves a temporary increase in new neuron formation. This compensatory increase is dissociated from glucocorticoid levels as well as from the restoration of normal sleep patterns. Collectively, these findings suggest that, although sleep deprivation inhibits adult neurogenesis by acting as a stressor, its compensatory aftereffects involve glucocorticoid-independent factors."

Memory enhancement during your sleep...just wear an electric head strap?

I'm wondering how long it is going to be before we start seeings advertisements for "effortless memory enhancement" devices inspired by the work of Marshall et al reported in Nature. (For example, a tiara that places button electrodes bilaterally over the mastoids and frontolateral cortex and generates a low oscillating current around 0.75 cycles per second during non-REM sleep). Although I'm tempted to cook down their description to make it a bit more palatable, their abstract does do the job:

"There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz—another frequency band that normally predominates during rapid-eye-movement sleep—decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space."