Nicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABA(A) receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP.

Aversive associative memories formed by the association between a neutral conditioned stimulus (CS+) and an aversive unconditioned stimulus (US+) are progressively made permanent by a process of consolidation 1 . However upon retrieval, intervention by amnestic agents [2][3][4][5][6][7] , either prior to or immediately after retrieval, results in disruption of the previously consolidated fear memory. This suggests that a consolidated memory returns to a transient destabilized state shortly after reactivation necessitating a dynamic time-dependent process of reconsolidation in order to persist further. During this reconstruction, a memory is vulnerable to experimental intervention [8][9][10] leading to amnesia, but can also be enhanced [11][12][13] or modified on the long-term [14][15][16] , thereby updating the previous memory with new information [14][15][16][17] . In clinical terms, the bidirectional and adaptive nature of reconsolidation is ideally placed to mediate both the modification of memory strength 12 , as well as memory content 16,18 , rendering this process a promising therapeutical target to counteract the hyper-responsive fear system. In order to fully exploit reconsolidation-based therapies that adapt the content of fear memories, leading to a loss of fear response on the long term, it is crucial to elucidate the molecular underpinnings of reconsolidation, which to this date remain obscure.3 Long-lasting changes in synaptic efficacy brought about by gene transcription, protein synthesis and changes in strength of hippocampal glutamatergic synapses via AMPA receptor trafficking are believed to be the cellular substrates of learning and memory [19][20][21] . Although reconsolidation is not merely a recapitulation of the initial consolidation process 22 , it has been shown that transcription, de novo protein synthesis and synaptic protein degradation in the hippocampus are also necessary for memory remodeling after retrieval 4,7,17,[23][24][25] . Here, we investigated whether the temporal profile of reconsolidation that is hypothesized to be limited to a 6 h time window 5,8 actuates a sequential profile of defined dorsohippocampal AMPA receptor synaptic plasticity that is crucial to the synaptic remodeling that underlies subsequent fear expression (changes in memory strength) and reinterpretation of fear memory after retrieval (changes in memory content). Results Memory recall induces acute hippocampal AMPAR-endocytosisIn order to analyze whether glutamate receptors are regulated during reconsolidation in animals receiving the US+ and retrieval (US-R), we dissected the dorsal hippocampus at 1 and 4 h post-retrieval, and analyzed the synaptic membrane fraction, including membrane-bound proteins and associated proteins 26,27 , by immunoblotting for subunits of AMPA receptors. A no-shock group experiencing retrieval (NS-R) was used to control for the specificity of an aversive-associative memory (Supplementary Fig. S1). These two time points were chosen as they fall within the 6-h time window after ret...

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.

In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2–4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission.

More than one-third of all people are estimated to experience mild to severe cognitive impairment as they age. Acetylcholine (ACh) levels in the brain diminish with aging, and nicotinic ACh receptor (nAChR) stimulation is known to enhance cognitive performance. The prefrontal cortex (PFC) is involved in a range of cognitive functions and is thought to mediate attentional focus. We found that mice carrying nAChR β2-subunit deletions have impaired attention performance. Efficient lentiviral vector-mediated reexpression of functional β2-subunit-containing nAChRs in PFC neurons of the prelimbic area (PrL) completely restored the attentional deficit but did not affect impulsive and motivational behavior. Our findings show that β2-subunit expression in the PrL PFC is sufficient for endogenous nAChR-mediated cholinergic regulation of attentional performance.

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The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.