The Sleep-Wake Cycle Regulates Extracellular Tau

Post by: Amanda McFarlan

What's the science?

The aggregation of hyperphosphorylated tau protein is one of the primary markers of Alzheimer’s disease and is known to be highly correlated with neuronal and synaptic degeneration. Previous studies have shown that neurons release tau protein into the extracellular space–where it can spread from one synapse to another—and that this release is increased with elevated neuronal activity. Since the state of wakefulness, compared to sleep, is associated with increased activity, the authors hypothesized that tau may be regulated by the sleep-wake cycle. This week in Science, Holth and colleagues investigated the effect of the sleep-wake cycle on tau in rodents and humans.

How did they do it?

The authors used in vivo microdialysis to examine the effect of the sleep-wake cycle on tau and lactate (regulated by neuronal activity) levels in the brain interstitial fluid in freely behaving mice. To do this, they surgically implanted a guide cannula into the left hippocampus of wild-type mice, and after recovery, inserted a microdialysis probe to collect brain interstitial fluid samples. The levels of tau and lactate in the brain interstitial fluid were then measured in mice that underwent one of three conditions: undisturbed sleep-wake cycle (control), manual sleep deprivation, and sleep deprivation with the infusion of tetrodotoxin (reduces neuronal activity). They further tested the effect of elevated wakefulness (sleep deprivation) on interstitial fluid tau and amyloid-β levels using chemogenetic activation (DREADDs) of the brain wake circuitry. Next, the authors investigated the effect of a longer period of sleep deprivation on the ability of injected tau fibrils to seed tau pathology as well as the ability of seeded tau pathology to proliferate in the brain and promote the misfolding of other tau proteins (tau spreading). They used a transgenic mouse model of tauopathy (P301S mice) and injected recombinant human tau fibrils into the hippocampus of young male mice (not yet expressing a tau pathology). Mice underwent either 28 days of sleep deprivation using the modified multiple platform technique or a control condition. Immunohistochemistry analyses were performed to determine whether tau aggregates had spread throughout the brain. Based on their results in mice, the authors also examined the effect of the sleep deprivation on tau levels in the cerebrospinal fluid of humans. A lumbar catheter was used to collect cerebrospinal fluid in adult participants as they underwent one night of normal rest and one night of sleep deprivation. The authors also measured levels of α-synuclein (a protein associated with increased neuronal activity) as well as other neuronal and glial proteins in the cerebrospinal fluid.

What did they find?

The authors determined that tau and lactate levels in the brain interstitial fluid were higher in control mice during the period of wakefulness compared to the period of sleep. They found that sleep deprivation caused an even greater increase in tau and lactate levels in the brain interstitial fluid. In mice that were both sleep deprived and infused with tetrodotoxin (reducing neuronal activity), there were no detectable changes in tau or lactate levels in the brain interstitial fluid. They also showed that increasing wakefulness using DREADDs significantly increased tau and amyloid-β in the interstitial fluid. Together, these findings suggest that higher tau levels during wakefulness and sleep deprivation might be a result of tau secretion due to increases in neuronal metabolism and synaptic strength. Next, the authors revealed that longer periods of sleep deprivation did not alter the ability of tau fibrils to seed the misfolding of other tau proteins at the injection site, but did increase the spreading of tau pathology throughout the brain compared to control conditions. They determined that in sleep deprived animals, tau spread from the hippocampus to the locus coeruleus, a brain region involved in wakefulness, was increased. In human studies, the authors found that levels of tau and synuclein in the cerebrospinal fluid were significantly increased with a night of sleep deprivation compared to a normal night of sleep. These findings suggests that tauopathies in humans might be sensitive to the sleep-wake cycle and in particular, sleep deprivation.


What's the impact?

This is the first study to show that levels of tau in the brain interstitial fluid are modulated by the sleep-wake cycle and increased with sleep deprivation in rodents. Furthermore, the authors showed that prolonged sleep deprivation in mice significantly increases tau spreading in the brain. Similarly, sleep deprivation was shown to increase tau levels in cerebrospinal fluid in humans. Altogether, this study provides evidence for a role of sleep and wake in regulating tau and tau pathology.


Holth et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science (2019). Access the original scientific publication here.

Cholinergic Interneurons in the Nucleus Accumbens Inhibit Reward-Seeking Behavior

Post by Shireen Parimoo

What's the science?

The nucleus accumbens (NAc), located in the midbrain, regulates motivational or reward-seeking behavior primarily through dopaminergic signaling. For example, dopaminergic activity increases in response to cues that signal an upcoming reward, such as a tone signaling that food will be arriving soon. Conversely, activation of cholinergic interneurons in the NAc is associated with the inhibition of reward-seeking behavior when this behavior might not be beneficial, like seeking food when already full. However, the causal role of these interneurons in regulating cue-motivated behavior is not well-understood. This week in Biological Psychiatry, Collins and colleagues used behavioral conditioning and a combination of optogenetic and chemogenetic techniques to investigate the causal role of cholinergic NAc interneurons in cue-motivated behavior.

How did they do it?

Adult transgenic rats were were injected with adeno-associated virus carrying channelrhodopsin (ChR2) or a control yellow fluorescent protein, and the human M4 muscarinic receptor (hM4D(Gi)) or the control mCherry, which were selectively expressed in the NAc interneurons. Optical stimulation of ChR2 increases interneuron activity, whereas clozapine N-oxide (CNO) injection inactivates interneurons by binding to hM4D(Gi). Cue-motivated behavior was measured using the Pavlovian-to-instrumental transfer (PIT) test, which consisted of a training and a test phase. In the training phase, the rats underwent 8 days each of Pavlovian and instrumental conditioning. For Pavlovian conditioning, a predictive tone cue was repeatedly paired with a chocolate pellet reward; for instrumental conditioning, pressing a lever resulted in a chocolate pellet reward, but no tone was present. Rats were also exposed to a neutral tone in the absence of any rewards during a single session.

In the PIT test phase, the rats were presented with the neutral and reward-predictive cues. They had access to a lever but pressing it did not result in a reward. The authors tested the effect of cholinergic interneuron inactivation on cue-motivated behavior (i.e. lever-pressing) by injecting the rats with CNO or a vehicle and examining behavior before (baseline) and after cue presentation. They optically stimulated the interneurons at cue presentation to test the effect of interneuron activation on behavior. Finally, they injected DhbE into the NAc, which is an acetylcholine antagonist that binds to b2-containing nicotinic receptors. They then optogenetically stimulated the interneurons and recorded cue-motivated behavior to determine whether acetylcholine released from the interneurons acts on nicotinic receptors to regulate cue-motivated behavior.

What did they find?

When the reward predictive cue was presented, both the hM4D(Gi) and control rats had more lever presses compared to baseline or when the neutral cue was presented. However, the hM4D(Gi) rats showed much greater lever-pressing behavior compared to controls when CNO was administered (i.e. when interneuron activity was reduced). Optogenetic activation of cholinergic interneurons led to greater acetylcholine release in ChR2-expressing rats, which was accompanied by a reduction in reward-seeking behavior in ChR2-expressing rats but not in control rats. This means that inhibiting cholinergic interneurons increases cue-motivated behavior, whereas activating the interneurons reduces cue-motivated behavior. Lastly, in the absence of any stimulation, rats infused with an acetylcholine antagonist or a vehicle (control condition) showed greater lever-pressing behavior in response to the predictive cue, but not at baseline or in response to the neutral cue. However, when the cholinergic interneurons were optically activated, there was a reduction in cue-motivated behavior among rats infused with the vehicle, but no change in response to the cue among rats infused with the acetylcholine antagonist. Thus, even though the activation of interneurons normally decreases cue-motivated behavior, an acetylcholine antagonist disrupts the downstream effects of these interneurons by blocking the interaction between acetylcholine and b2-containing nicotinic receptors.


What's the impact?

This study demonstrates that nucleus accumbens cholinergic interneurons have an inhibitory effect on cue-motivated behavior and regulate this behavior by acting on downstream nicotinic receptors. These findings provide further insight into our current understanding of psychiatric conditions with dysfunctional motivational behavior, such as eating disorders and addiction, and have important implications for developing treatments for such disorders.


Collins et al. Nucleus accumbens cholinergic interneurons oppose cue-motivated behavior. Biological Psychiatry (2019). Access the original scientific publication here.

Dopamine Modulates the Reward Experiences Elicited by Music

Post by Flora Moujaes

What's the science?

Humans experience pleasure from abstract rewards, such as music, that do not confer any direct advantage for survival. Understanding how the brain translates music, a sequence of sounds, into a pleasant rewarding experience remains a challenge. Reward can be divided into three neurobiologically distinct components: hedonic pleasure (in-the-moment liking), motivation (or wanting), and learning. The role of dopamine in motivation and learning has been widely established in the animal literature, but dopamine’s function in hedonic pleasure is more controversial. Animal literature has tended to focus on primary rewards such as food and sex, rather than abstract rewards such as music. This week in PNAS, Ferreri and colleagues used a pharmacological intervention to explore for the first time whether dopamine function is causally related to the pleasure we experience from music, and how it influences both hedonic pleasure and motivation.

How did they do it?

Researchers manipulated dopamine transmission in 27 human participants while they listened to music in three different sessions, each at least a week apart. The authors began by orally administering either levodopa (a dopamine enhancer), risperidone (a dopamine blocker), or lactose (a placebo). Participants then listened to five of their favourite musical excerpts and 10 pop songs selected by the experimenters, which included a range of artists from Antonio Orozco to Taylor Swift. Pleasure responses were measured continuously 1) by participants indicating in real-time the degree of pleasure they were experiencing and 2) by measuring electrodermal activity: changes in the electrical properties of the skin that are related to emotional arousal. Motivational responses were measured using an auction paradigm, where participants indicated how much money they were willing to part with to buy the song. Finally, participants also completed a well-validated reward control task (the Monetary Incentive Delay Task) in order to verify that any changes caused by dopamine were related to the reward system, and not more general processes.

What did they find?

Researchers predicted that if dopamine plays a causal role in music-evoked reward, enhancing dopamine through levodopa and reducing dopamine through risperidone should lead to opposite effects regarding musical pleasure and motivation. In line with their prediction, they found that administration of levodopa and risperidone led to opposite effects: levodopa led to an increase in the experience of ‘chills’ or goose bumps, a common indicator of musical pleasure, while risperidone resulted in a decrease in chills. Electrodermal activity and participants’ ratings also indicated that they experienced an increase in pleasure when listening to music following dopamine enhancement and a decrease in pleasure following dopamine impairment. In contrast to much of the animal literature, this suggests that dopamine causally influences the hedonic pleasure experienced while listening to music. Participants bid significantly more money for songs under levodopa than risperidone, indicating that dopamine is also causally involved in motivational reward responses. The dopamine-induced changes in reward responses were paralleled by those observed in the control Monetary Incentive Delay task, suggesting that the effects seen while listening to music were a result of dopamine’s modulation of the reward system rather than of more general processes.


What's the impact?

This study is the first to show that dopamine function is causally related to the pleasure we experience from music, influencing both hedonic pleasure and motivation. More broadly, these findings begin to shed light on the more complex role the human dopaminergic system plays in abstract rewards. Musical pleasure also depends on additional affective and abstract cognitive processes (e.g. episodic memory). Given these additional processes also rely on dopaminergic transmission, further research is needed to determine whether dopamine generates the hedonic and motivational responses to music or whether it interacts with other neurotransmitter systems (e.g. the opioid system) to generate such responses.


Ferreri et al. Dopamine modulates the reward experiences elicited by music. PNAS (2019). Access the original scientific publication here.