Pattern separation is a computational process whereby potentially similar memory representations are made as dissimilar as possible at the time of encoding. The complementary process, pattern completion, is the process whereby memory representations are...

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication, cognitive rigidity, and atypical sensory processing. Recent studies suggest that the basal ganglia, specifically the striatum (NSt), plays an important role in ASD. While striatal interneurons, including cholinergic (ChAT+) and parvalbumin-positive (PV+) GABAergic neurons, have been described to be altered in animal models of ASD, their specific contribution remains elusive. Here, we combined behavioral, anatomical, and electrophysiological quantifications to explore if interneuron balance could be implicated in atypical sensory processing in cortical and striatal somatosensory regions of rats subjected to a valproic acid (VPA) model of ASD. We found that VPA animals showed a significant decrease in the number of ChAT+ and PV+ cells in multiple regions (including the sensorimotor region) of the NSt. We also observed significantly different sensory-evoked responses at the single-neuron and population levels ...

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [( S )-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4 H -[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measure...

Difficult decisions and optimism for the future.

Monkey inferotemporal cortex (ITC) neurons respond with declining strength to repeated presentations of a large and complex natural image. This phenomenon - repetition suppression - has often been assumed to arise at the level of ITC because ITC neurons...

Objectives: We conducted a psychophysical study to determine whether the emotional content of priming images presented subliminally (so briefly that they could not be consciously perceived) affected the subsequent perception of facial expressions. Metho...

Recognizing an object is usually faster and more accurate if that object has been encountered previously. Such experience-based priming of recognition can also be achieved through context-specific predictions about which objects are likely to appear together in a specific scene. Seeing a toaster, for instance, can facilitate subsequent recognition of contextually related objects such as a coffee-maker and a blender. The benefit of priming during recognition is typically associated with a physiological response reduction in occipito-temporal cortex. Moreover, the specific regions that exhibit response reduction in priming tasks can vary according to the nature of the relation between the target- and preceding prime-objects. Using event-related fMRI, we sought to elaborate the cortical mechanisms involved in experience-based facilitation of object recognition. Thus, we compared the different foci of response reductions for targets preceded by primes that were either the same object or were contextually relat...

Knowing how reward-associated cues influence instrumental behaviors is important for understanding many aspects of motivated behavior, including pathological states of motivation such as addiction. A prime example of this is the Pavlovian-to-instrumental transfer phenomenon (or PIT). In this procedure, after animals learn to associate a Pavlovian cue with reward (CS+) and, on separate occasions, learn to instrumentally respond for this reward, presentation of the CS+ during instrumental performance typically potentiates responding. Although little is known about the neurobiology of PIT, studies have clearly implicated glutamatergic (AMPA) and dopaminergic mechanisms. For instance, pretreatment with D1/D2-like (α-flupenthixol or Pimozide) antagonists was reported to disrupt PIT in rats (Dickinson et al, 2000). Here we further explore the role of dopamine receptor activation in PIT by pretreating C57/b6 mice, 10 min prior to PIT testing, with different IP doses of D1 or D2 receptor antagonists. We report tha...

Many women with epilepsy experience cycle-related increased seizure susceptibility, correlated with low progesterone levels, termed catamenial epilepsy. Recurring fluctuations in the levels of neurosteroids are prime candidates for mediating changes in neuronal excitability over the ovarian cycle, but the precise mechanisms responsible for their actions have yet to be elucidated. Progesterone metabolites are known to be potent modulators of GABAA receptors (GABAARs) and tonic inhibition mediated by δ subunit-containing GABAARs is an important site of action of neurosteroids. We have previously shown that changes in GABAARs δ subunit expression during the estrous cycle in mice accompany cyclic changes in seizure susceptibility and anxiety. The GABAR agonist THIP at low concentrations acts selectively at δ subunit-containing GABAARs to enhance the tonic GABAergic inhibition in dentate gyrus granules cells. When tested for its anticonvulsant activity in vivo against kainic acid-induced seizures, i.p. administ...

Neuronal activity induces a hierarchical program of mRNA transcription that involves both immediate early (IEG) and delayed early genes (DERG) that are hypothesized to underlie learning-dependent neuronal plasticity (Lanahan & Worley, 1998). IEGs are transcribed within minutes of a novel learning experience, as can be visualized by the technique known as cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH). Despite the wealth of data generated on IEG expression, relatively little is known about DERGs. This class of genes shows stimulus-dependent transcriptional induction similar to IEGs; however, an initial wave of transcription and de novo protein synthesis is necessary in order for the DERGs to be transcribed (Goelet et al., 1986). DERGs are implicated in mediating long-term changes in cell function in many non-neuronal systems. Thus, these gene products are a prime candidate for mediating long-term functional changes associated with learning and memory. Desp...