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SUMMARYReward and punishment powerfully inform ongoing behaviors and drive learning throughout the brain, including neocortex. Yet it remains elusive how these global signals are represented and impact local cortical computations. Previously we found that in auditory cortex, VIP-expressing interneurons are recruited by reinforcement feedback. Here, we used 3D random-access two-photon microscopy and fiber photometry to monitor VIP neural activity in dozens of cortical areas while mice learned an auditory decision task. We show that reward and punishment evoke a rapid, cortex-wide activation of most VIP interneurons. This global recruitment mode of VIP interneurons showed variations in temporal dynamics in individual neurons and across areas. Neither their weak sensory tuning in visual cortex, nor their arousal state modulation was predictive of reinforcer responses of VIP interneurons. We suggest that VIP-expressing cortical inhibitory neurons transduce global reinforcement signals to provide disinhibitory control over local circuit computations and their plasticity.

In the classical view of economic choices, subjects make rational decisions evaluating the costs and benefits of options in order to maximize their overall income. Nonetheless, subjects often fail to reach optimal outcomes. The overt value of an option drives the direction of decisions, but covert factors such as emotion and sensitivity to sunk cost are thought to drive the observed deviations from optimality. Many questions remain to be answered as to (1) which contexts contribute the most to deviation from an optimal solution; and (2) the extent of these effects. In order to tackle these questions, we devised a decision-making task for mice, in which cost and benefit parameters could be independently and flexibly adjusted and for which a tractable optimal solution was known. Comparing mouse behavior with this optimal solution across parameter settings revealed that the factor most strongly contributing to suboptimal performance was the cost parameter. The quantification of sensitivity to sunk cost, a covert factor implicated in our task design, revealed it as another contributor to reduced optimality. In one condition where the large reward option was particularly unattractive and the small reward cost was low, the sensitivity to sunk cost and the cost-led suboptimality almost vanished. In this regime and this regime only, mice could be viewed as close to rational (here, ‘rational’ refers to a state in which an animal makes decisions basing on objective valuation, not covert factors). Taken together, our results suggest that “rationality” is a task-specific construct even in mice.

Background Working memory deficits are key cognitive symptoms of schizophrenia. Elevated delta oscillations, which are uniquely associated with the presence of the illness, may be the proximal cause of these deficits. Spatial working memory (SWM) is impaired by elevated delta oscillations projecting from thalamic nucleus reuniens (RE) to the hippocampus (HPC); these findings imply a role of the RE-HPC circuit in working memory deficits in schizophrenia, but questions remain as to whether the affected process is the encoding of working memory, recall, or both. Here, we answered this question by optogenetically inducing delta oscillations in the HPC terminals of RE axons in mice during either the encoding or retrieval phase (or both) of an SWM task. Methods We transduced cells in RE to express channelrhodopsin-2 through bilateral injection of adeno-associated virus, and bilaterally implanted optical fibers dorsal to the hippocampus (HPC). While mice performed a spatial memory task on a Y-maze, the RE-HPC projections were optogenetically stimulated at delta frequency during distinct phases of the task. Results Full-trial stimulation successfully impaired SWM performance, replicating the results of the previous study in a mouse model. Task-phase-specific stimulation significantly impaired performance during retrieval but not encoding. Conclusions Our results indicate that perturbations in the RE-HPC circuit specifically impair the retrieval phase of working memory. This finding supports the hypothesis that abnormal delta frequency bursting in the thalamus could have a causal role in producing the WM deficits seen in schizophrenia.

In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation. Although several interneuron populations are known to target other interneurons to varying degrees, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.

CaMKII is an abundant synaptic protein strongly implicated in plasticity. Overexpression of autonomous (T286D) CaMKII in CA1 hippocampal cells enhances synaptic strength if T305/T306 sites are not phosphorylated, but decreases synaptic strength if they are phosphorylated. It has generally been thought that spine size and synaptic strength covary; however, the ability of CaMKII and its various phosphorylation states to control spine size has not been previously examined. Using a unique method that allows the effects of overexpressed protein to be monitored over time, we found that all autonomous forms of CaMKII increase spine size. Thus, for instance, the T286D/T305D/T306D form increases spine size but decreases synaptic strength. Further evidence for such dissociation is provided by experiments with the T286D form that has been made catalytically dead. This form fails to enhance synaptic strength but increases spine size, presumably by a structural process. Thus very different mechanisms govern how CaMKII affects spine structure and synaptic function.

The N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia is based on the ability of NMDAR antagonists to produce many symptoms of the disease. Recent work in rats shows that NMDAR antagonist works synergistically with dopamine to produce delta frequency bursting in the thalamus. This finding, together with other results in the literature, suggests a mechanism for the sudden onset of schizophrenia. Among the thalamic nuclei most activated by NMDAR antagonist is the nucleus reuniens. This nucleus excites the cornu ammonis area 1 (CA1) region of the hippocampus. Experiments indicate that such activation can lead to excitation of dopaminergic cells of the ventral tegmental area by a polysynaptic pathway. The resulting elevation of dopamine in the thalamus will enhance thalamic bursting, thereby creating a loop with the potential for positive feedback. We show through computer simulations that in individuals with susceptibility to schizophrenia (e.g., because of partially compromised NMDAR function), an event that stimulates the dopamine system, such as stress, can cause the system to reach the threshold for thalamic bursting. When this occurs, positive feedback in the loop will cause all components to become highly active and to remain active after the triggering stimulus is removed. This is a physiologically specific hypothesis for the sudden and lasting transition that underlies the psychotic break in schizophrenia. Furthermore, the model provides an explanation for the observed selective activation of the CA1 hippocampal region in schizophrenia. The model also predicts an increase of basal activity in the dopamine system and thalamus; the relevant evidence is reviewed.

Studies of long-term potentiation (LTP) and long-term depression (LTD) strongly suggest that individual synapses can be bidirectionally modified. A central question is the biochemical mechanisms that make LTP and LTD persistent. Previous theoretical models have proposed that the autophosphorylation properties of CaMKII could underlie a bistable molecular switch that maintains LTP, and there is experimental support for this mechanism. In contrast, there has been comparatively little theoretical or experimental work regarding the mechanisms that maintain LTD. Several lines of evidence indicate that LTD is not simply a reversal of previous LTP but rather involves separate biochemical reactions. These findings indicate that a minimal model of the synapse must involve a tristable system. Here, we describe a phosphatase (PP2A) switch, which together with a kinase switch form a tristable system. PP2A can be activated by a Ca2+-dependent process but can also be phosphorylated and inactivated by CaMKII. When dephosphorylated, PP2A can dephosphorylate itself. We show that these properties can lead to a persistent increase in PP2A during LTD (as reported experimentally), thus forming a phosphatase switch. We show that the coupled PP2A and CaMKII switches lead to a tristable system in which the kinase activity is high in the LTP state; the PP2A activity is high in the LTD state, and neither activity is high in the basal state. Our results provide an explanation for the recent finding that inhibition of PP2A prevents LTD induction.

The cellular diversity of interneurons in the neocortex is thought to reflect subtype-specific roles of cortical inhibition. Here we ask whether perturbations to two subtypes—parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons—can be compensated for with respect to their contributions to cortical development. We use a genetic cell fate switch to delete both PV+ and SST+ interneurons selectively in cortical layers 2–4 without numerically changing the total interneuron population. This manipulation is compensated for at the level of synaptic currents and receptive fields (RFs) in the somatosensory cortex. By contrast, we identify a deficit in inhibitory synchronization in vitro and a large reduction in cortical gamma oscillations in vivo. This reveals that, while the roles of inhibition in establishing cortical inhibitory/excitatory balance and RFs can be subserved by multiple interneuron subtypes, gamma oscillations depend on cellular properties that cannot be compensated for—likely, the fast signalling properties of PV+ interneurons., The neocortex contains a large diversity of interneurons but the subtype-specific roles of these cells in establishing excitatory and inhibitory circuits are not well understood. Here the authors genetically delete parvalbumin- and somatostatin-positive interneurons during mouse development and study the functional effects in postnatal cortical circuits.

The exquisite architecture of cortex incorporates a myriad of inhibitory interneuron types. Until recently, the dearth of techniques for cell type identification in awake animals has made it difficult to link interneuron activity with circuit function, computation and behavior. This situation has changed dramatically in recent years with the advent of novel tools for targeting genetically distinct interneuron types so their activity can be observed and manipulated. The association of different interneuron subtypes with specific circuit functions, such as gain modulation or disinhibition, is starting to reveal canonical circuit motifs conserved across neocortical regions. Moreover, it appears that some interneuron types are recruited at specific behavioral events and likely control the flow of information among and within brain areas at behavioral time scales. Based on these results we propose that interneuron function goes beyond network coordination and interneurons should be viewed as integral elements of cortical computations serving behavior.

Ca(2+)/calmodulin-dependent kinase II (CaMKII) is a key mediator of long-term potentiation (LTP). Whereas acute intracellular injection of catalytically active CaMKII fragments saturates LTP (Lledo et al., 1995), an autonomously active form (T286D) of CaMKII holoenzyme expressed in transgenic mice did not saturate potentiation (Mayford et al., 1995). To better understand the role of the holoenzyme in the control of synaptic strength, we transfected hippocampal neurons with constructs encoding forms of CaMKII mimicking different phosphorylation states. Surprisingly, T286D not only failed to potentiate synaptic strength, but produced synaptic depression through an long-term depression (LTD)-like process. T305/T306 phosphorylation was critical for this depression because overexpression of the pseudophosphorylated form (T286D/T305D/T306D) caused depression that occluded LTD, and overexpression of an autonomous form in which T305/T306 could not be phosphorylated (T286D/T305A/T306A) prevented LTD (instead producing potentiation). Therefore, autonomous CaMKII can lead to either LTP or LTD, depending on the phosphorylation state of the control point, T305/T306.

Standing wave patterns that arise on the surface of ferrofluids by (single frequency) parametric forcing with an ac magnetic field are investigated experimentally. Depending on the frequency and amplitude of the forcing, the system exhibits various patterns including a superlattice and subharmonic rhombuses as well as conventional harmonic hexagons and subharmonic squares. The superlattice arises in a bicritical situation where harmonic and subharmonic modes collide. The rhombic pattern arises due to the non-monotonic dispersion relation of a ferrofluid.

SummarySerotonin dysfunction is implicated in many neuropsychiatric disorders yet the precise behavioral functions of this neuromodulator are not well understood. A new study employs optogenetic methods to activate serotonin neurons during an effort-demanding waiting behavior and demonstrates that serotonin release increases patience, the capacity for self-control.