To efficiently process information, the brain shifts between encoding and retrieval states, prioritizing bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI, we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events' expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected s...

It is a commonly accepted view that light stimulation of mammalian photoreceptors causes a graded change in membrane potential instead of developing a spike. The presynaptic Ca2+ channels serve as a crucial link for the coding of membrane potential variations into neurotransmitter release. Cav1.4 L-type Ca2+ channels are expressed in photoreceptor terminals, but the complete pool of Ca2+ channels in cone photoreceptors appears to be more diverse. Here, we discovered, employing whole-cell patch-clamp recording from cone photoreceptor terminals in both sexes of mice, that their Ca2+ currents are composed of low- (T-type Ca2+ channels) and high- (L-type Ca2+ channels) voltage-activated components. Furthermore, Ca2+ channels exerted self-generated spike behavior in dark membrane potentials, and spikes were generated in response to light/dark transition. The application of fast and slow Ca2+ chelators revealed that T-type Ca2+ channels are located close to the release machinery. Furthermore, capacitance measure...

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein ( APP ), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP ; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation ( AppNL-F ) to determine how chromosome 21 genes, other than APP , modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aβ accumulation and ...

Dyrk1a triplication in Down's syndrome and its overexpression in Alzheimer's disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer's disease, which lead to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in human neurons remains unknown. From a proteomic dataset of human cerebral organoids treated with harmine, a DYRK1A inhibitor, we found expression changes in protein clusters associated with the control of microtubule-based transport and in close interaction with the APP vesicle. Live imaging of APP axonal transport in human-derived neurons treated with harmine or overexpressing a dominant negative DYRK1A revealed a reduction in APP vesicle density and enhanced the stochastic behavior of retrograde vesicle transport. Moreover, harmine increased the fraction of slow segmental velocities and changed speed transitions supporting a DYRK1A-media...

Adaptive behavior requires the ability to appropriately react to action errors. Post-error slowing of response times (PES) is one of the most reliable phenomena in human behavior. It has been proposed that PES is partially achieved through inhibition of the motor system. However, there is no direct evidence for this link – or indeed, that the motor system is physiologically inhibited after errors altogether. Here, we used transcranial magnetic stimulation and electromyography to measure cortico-spinal excitability (CSE) across four experiments using a Simon task, in which female and male human participants sometimes committed errors. Errors were followed by reduced CSE at two different time points and in two different modes. Shortly after error commission (250ms) CSE was broadly suppressed – i.e., even task-unrelated motor effectors were inhibited. During the preparation of the subsequent response, CSE was specifically reduced at task-relevant effectors only. This latter effect was directly related to PES,...

Forgetting is important for animals to manage acquired memories to enable adaptation to changing environments; however, the neural network in mechanisms of forgetting is not fully understood. To understand the mechanisms underlying forgetting, we examined olfactory adaptation, a form of associative learning, in Caenorhabditis elegans ( C. elegans ). The forgetting of diacetyl olfactory adaptation in C. elegans is regulated by secreted signals from AWC sensory neurons via the TIR-1/JNK-1 pathway. These signals cause a decline of the sensory memory trace in AWA neurons where diacetyl is mainly sensed. To further understand the neural network that regulates this forgetting, we investigated the function of interneurons downstream of AWA and AWC neurons. We found that a pair of interneurons, AIA, is indispensable for the proper regulation of behavioral forgetting of diacetyl olfactory adaptation. Loss of or inactivation of AIA caused the impairment of the chemotaxis recovery after adaptation without causing sev...

The habenula is an evolutionarily conserved structure of the vertebrate brain that is essential for behavioural flexibility and mood control. It is spontaneously active and is able to access diverse states when the animal is exposed to sensory stimuli. Here we investigate the dynamics of habenula spontaneous activity, to gain insight into how sensitivity is optimized. Two-photon calcium imaging was performed in resting zebrafish larvae at single cell resolution. An analysis of avalanches of inferred spikes suggests that the habenula is subcritical. Activity had low covariance and a small mean, arguing against dynamic criticality. A multiple regression estimator of autocorrelation time suggests that the habenula is neither fully asynchronous nor perfectly critical, but is reverberating. This pattern of dynamics may enable integration of information and high flexibility in the tuning of network properties, thus providing a potential mechanism for the optimal responses to a changing environment. Significance...

While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence. We aimed to investigate whether cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses. Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated DRG neurons. Blood oxygen saturation, locomotion, and defecation were measured to evaluate side effects. An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2′-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1...

Adam Davison, Uwe Thorsten Lux, Johann Helmut Brandstätter, Norbert Babai (see pages [6325–6343][1]) Cone photoreceptors are hyperpolarized in light and become depolarized as the light dims. The depolarization spreads passively to the axon terminal, where it causes voltage-activated calcium