If I do A, B will happen: Dissecting circuits detecting causal relations between actions and outcomes in marmoset prefrontal cortex

Top-Down Control-Signal Dynamics in Anterior Cingulate and Prefrontal Cortex Neurons following Task Switching

Individual Differences in Subconscious Motor Control Predicted by GABA Concentration in SMA

Distributed Coding of Actual and Hypothetical Outcomes in the Orbital and Dorsolateral Prefrontal Cortex

Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP regulates local protein synthesis in dendritic spines. Dopamine (DA) is involved in the modulation of synaptic plasticity. Activation of DA receptors can regulate higher brain functions in a protein synthesis-dependent manner. Our recent study has shown that FMRP acts as a key messenger for DA modulation in forebrain neurons. Here, we demonstrate that FMRP is critical for DA D1 receptor-mediated synthesis of synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) in the prefrontal cortex (PFC). DA D1 receptor stimulation induced dynamic changes of FMRP phosphorylation. The changes in FMRP phosphorylation temporally correspond with the expression of SAPAP3 after D1 receptor stimulation. Protein phosphatase 2A, ribosomal protein S6 kinase, and mammalian target of rapamycin are the key signaling molecules for FMRP linking DA D1 receptors to SAPAP3. Knockdown of SAPAP3 did not affect surface expression of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) GluR1 receptors induced by D1 receptor activation but impaired their subsequent internalization in cultured PFC neurons; the subsequent internalization of GluR1 was also impaired in Fmr1 knock-out PFC neurons, suggesting that FMRP may be involved in subsequent internalization of GluR1 through regulating the abundance of SAPAP3 after DA D1 receptor stimulation. Our study thus provides further insights into FMRP involvement in DA modulation and may help to reveal the molecular mechanisms underlying impaired learning and memory in fragile X syndrome.

Economic choices between goods are thought to rely on the orbitofrontal cortex (OFC), but the decision mechanisms remain poorly understood. To shed light on this fundamental issue, we recorded from the OFC of monkeys choosing between two juices offered sequentially. An analysis of firing rates across time windows revealed the presence of different groups of neurons similar to those previously identified under simultaneous offers. This observation suggested that economic decisions in the two modalities are formed in the same neural circuit. We then examined several hypotheses on the decision mechanisms. OFC neurons encoded good identities and values in a juice-based representation (labeled lines). Contrary to previous assessments, our data argued against the idea that decisions rely on mutual inhibition at the level of offer values. In fact, we showed that previous arguments for mutual inhibition were confounded by differences in value ranges. Instead, decisions seemed to involve mechanisms of circuit inhibition, whereby each offer value indirectly inhibited neurons encoding the opposite choice outcome. Our results reconcile a variety of previous findings and provide a general account for the neuronal underpinnings of economic choices.

Gating of Fear in Prelimbic Cortex by Hippocampal and Amygdala Inputs

Will Studies of Macaque Insula Reveal the Neural Mechanisms of Self-Awareness?

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Ketamine*

Learning Substrates in the Primate Prefrontal Cortex and Striatum: Sustained Activity Related to Successful Actions

How does the non-conscious become conscious?

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

Differential Neural Activation for Updating Rule versus Stimulus Information in Working Memory

Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function.

Emerging evidence indicates that amyloid β peptide (Aβ) initially induces subtle alterations in synaptic function in Alzheimer disease. We have recently shown that Aβ binds to β(2) adrenergic receptor (β(2)AR) and activates protein kinase A (PKA) signaling for glutamatergic regulation of synaptic activities. Here we show that in the cerebrums of mice expressing human familial mutant presenilin 1 and amyloid precursor protein genes, the levels of β(2)AR are drastically reduced. Moreover, Aβ induces internalization of transfected human β(2)AR in fibroblasts and endogenous β(2)AR in primary prefrontal cortical neurons. In fibroblasts, Aβ treatment also induces transportation of β(2)AR into lysosome, and prolonged Aβ treatment causes β(2)AR degradation. The Aβ-induced β(2)AR internalization requires the N terminus of the receptor containing the peptide binding sites and phosphorylation of β(2)AR by G protein-coupled receptor kinase, not by PKA. However, the G protein-coupled receptor kinase phosphorylation of β(2)AR and the receptor internalization are much slower than that induced by βAR agonist isoproterenol. The Aβ-induced β(2)AR internalization is also dependent on adaptor protein arrestin 3 and GTPase dynamin, but not arrestin 2. Functionally, pretreatment of primary prefrontal cortical neurons with Aβ induces desensitization of β(2)AR, which leads to attenuated response to subsequent stimulation with isoproterenol, including decreased cAMP levels, PKA activities, PKA phosphorylation of serine 845 on α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor subunit 1 (GluR1), and AMPA receptor-mediated miniature excitatory postsynaptic currents. This study indicates that Aβ induces β(2)AR internalization and degradation leading to impairment of adrenergic and glutamatergic activities.