Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

Summary The capacity for goal-directed action depends on encoding specific action-outcome associations, a learning process mediated by the posterior dorsomedial striatum (pDMS). In a changing environment plasticity has to remain flexible requiring interference between new and existing learning to be minimized, yet it is not known how new and existing learning are interlaced in this way. Here we investigated the role of the thalamo-striatal pathway linking the parafascicular thalamus (Pf) with cholinergic interneurons (CINs) in the pDMS in this process. Removing the excitatory input from Pf to the CINs was found to reduce the firing rate and intrinsic activity of these neurons and produced an enduring deficit in goal-directed learning after changes in the action-outcome contingency. Disconnection of the Pf – pDMS pathway produced similar behavioral effects. These data suggest that CINs reduce interference between new and existing learning, consistent with claims that the thalamo-striatal pathway exerts state control over learning-related plasticity.

Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex; however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions; consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes.

Non-technical summary The lower mid-brain of rodent is home to addiction and hedonism of substances of abuse. Due to overlapping physiological properties among different types of nerve cell within this brain region, it has been difficult to selectively study the physiology of a single type of nerve cell. Here, using gene technology together with selective antibody detection, we have exclusively identified the two dominant populations of nerve cells and found dopamine-containing cells five times more abundant. We found clear non-overlapping cellular characteristics between the two types that are unequivocal predictors for selection of nerve cells, whilst other previously employed cellular criteria were found to be less useful.Abstract The midbrain ventral tegmental area (VTA) contains neurons largely with either a dopaminergic (DAergic) or GABAergic phenotype. Physiological and pharmacological properties of DAergic neurons have been determined using tyrosine hydroxylase (TH) immunohistochemistry but many properties overlap with non-DAergic neurons presumed to be GABAergic. This study examined properties of GABAergic neurons, non-GABAergic neurons and TH-immunopositive neurons in VTA of GAD67-GFP knock-in mice. Ninety-eight per cent of VTA neurons were either GAD-GFP or TH positive, with the latter being five times more abundant. During cell-attached patch-clamp recordings, GAD-GFP neurons fired brief action potentials that could be completely distinguished from those of non-GFP neurons. Pharmacologically, the μ-opioid agonist DAMGO inhibited firing of action potentials in 92% of GAD-GFP neurons but had no effect in non-GFP neurons. By contrast, dopamine invariably inhibited action potentials in non-GFP neurons but only did so in 8% of GAD-GFP neurons. During whole-cell recordings, the narrower width of action potential in GAD-GFP neurons was also evident but there was considerable overlap with non-GFP neurons. GAD-GFP neurons invariably failed to exhibit the potassium-mediated slow depolarizing potential during injection of positive current that was present in all non-GFP neurons. Under voltage-clamp the cationic current, I h , was found in both types of neurons with considerable overlap in both amplitude and kinetics. These distinct cellular properties may thus be used to confidently discriminate GABAergic and DAergic neurons in VTA during in vitro electrophysiological recordings.

1 In this study we have examined the effects of nociceptin, an endogenous ligand for the opioid-like receptor ORLI, on the membrane properties of rat locus coeruleus (LC) neurones in vitro, using intracellular and whole cell patch clamp recording. 2 When locus coeruleus neurones were voltage clamped to -60 mV, application of nociceptin caused an outward current in all cells examined (n = 49), with an EC50 of 90 nm. Neither the potency nor the maximal effect of nociceptin was altered in the presence of the peptidase inhibitors, bestatin (20 gM) or thiorphan (2 pM). 3 The outward currents caused by nociceptin in 2.5 mM extracellular K+ reversed polarity at -123 mV, more negative than the predicted K+ reversal potential of -105 mV. Increasing extracellular K+ to 6.5 mM resulted in a shift of the reversal potential of + 25 mV, a shift consistent with a K+ conductance. The conductance activated by nociceptin showed mild inward rectification.4 Application of a high concentration of nociceptin (3 gM) occluded the current produced by simultaneous application of high concentrations of Met-enkephalin (10 gM), (3 uM) somatostatin and UK 14304 (3 gM), indicating that nociceptin activated the same conductance as p-opioid and somatostatin receptors and a2-adrenoceptors. 6 Dynorphin A (3 gM), another putative endogenous ligand for ORL,, caused a robust outward current in locus coeruleus neurones that was, however, completely antagonized by moderate concentrations of naloxone (300 nM-1 gM). 7 Continuous application of nociceptin (3 gM) resulted in a decrease of the outward current to a steady level of 70% of the maximum response with a t1/2 of 120s. Desensitization was largely homologous because simultaneous application of Met-enkephalin (30 gM) during the desensitized period of the nociceptin response resulted in an outward current that was 92% of control responses to Met-enkephalin in the same cells. Conversely, continuous application of Met-enkephalin (30 gM) resulted in a decrease of Met-enkephalin current to a steady level that was 54% of the initial current. During this desensitized period application of nociceptin (3 gM) resulted in a current that was 78% of the control responses to nociceptin in the same cells. 8 Thus nociceptin potently activates an inwardly rectifying K+ conductance in locus coeruleus neurones, with a pharmacological profile consistent with activation of the ORL, receptor. Dynorphin A does not appear to be a ligand for ORLI in rat locus coeruleus neurones.