NR2A- and NR2B-containing NMDA Receptors in the Prelimbic Medial Prefrontal Cortex Differentially Mediate Trace, Delay, and Contextual Fear Conditioning

Activation of N-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially regulate these two fear memories. Here we show that NR2A-containing NMDARs mediate trace, delay, and contextual fear memories, but NR2B-containing NMDARs are required only for trace conditioning, consistent with a role for PL mPFC in working memory

Prefrontal Activity Links Nonoverlapping Events in Memory

The medial prefrontal cortex (mPFC) plays an important role in memory. By maintaining a working memory buffer, neurons in prelimbic (PL) mPFC may selectively contribute to learning associations between stimuli that are separated in time, as in trace fear conditioning (TFC). Until now, evidence for this bridging role was largely descriptive. Here we used optogenetics to silence neurons in the PL mPFC of rats during learning in TFC. Memory formation was prevented when mPFC was silenced specifically during the interval separating the cue and shock. Our results provide support for a working memory function for these cells and indicate that associating two noncontiguous stimuli requires bridging activity in PL mPFC

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in The Prefrontal Cortex Modulates Cued Fear Learning, But Not Spatial Working Memory, in Female Rats

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues

Conformation of the anterior segment in human myopia.

PURPOSE: Topography of the in vivo anterior segment is of relevance in understanding its role in myopia and in the development of ocular surgical procedures. Using 3D magnetic resonance (MR) images of the human eye, regional variations in surface area (SA) and bulbosity of four anterior segment regions were investigated in association with refractive status (Rx), axial length (AL) and total ocular volume (OV). METHODS: T2-weighted ocular MR images from 43 adults aged 18-40 years (mean ± SD; 28.65 ± 6.20) comprising 20 non-myopes (≥-0.50) 0.57 ± 1.38 and 23 myopes (<-0.50) -6.37 ± 4.23 MSE (D) were collected. 2D representations of each quadrant (superior-temporal [ST], superior-nasal [SN], inferior-temporal [IT] and inferior-nasal [IN]) of the anterior section (3.5-9 mm) were fitted with second-order polynomials. Polynomials were integrated and rotated about the x-axis to generate SA; dividing the SA by 4 provided relative quadrantial SA. The x2 coefficient provides indices of bulbosity. OV was derived from the 3D MRI scans. Rx and AL were measured using cycloplegic autorefraction and the Zeiss IOLMaster, respectively. One- and two-way repeated-measures ANCOVAs tested differences in SA and bulbosity for Rx, gender, ethnicity and age. Pearson's correlation coefficient tested the relationship between MRI-derived metrics and biometry. RESULTS: Significant differences in SA were observed between quadrants (p < 0.001) with differences between ST versus IN, IN versus IT and SN versus IT. An interaction effect (p = 0.01) for Rx suggested smaller temporal (ST and IT) and larger nasal (SN and IN) SA in myopes. AL and myopic Rx were negative correlated (p < 0.05) with SA at IN, SN and IT. OV was significantly associated with SA at ST. Bulbosity showed no regional differences nor an effect of AL or Rx. CONCLUSION: Significant regional variation in SA exists across the anterior segment that is modulated by Rx and AL. It is unclear whether these structural characteristics are a precursor or consequence of myopia and may warrant investigation when developing biomechanical interventions

Prelimbic Input to Basolateral Amygdala Facilitates the Acquisition of Trace Cued Fear Memory Under Weak Training Conditions

The ability to predict the occurrence of an aversive outcome based on available cues requires associative learning and plastic changes in the amygdala. When the predictive cue and aversive shock outcome are separated in time as in trace fear conditioning, additional circuitry is needed, including the prelimbic (PL) area of the prefrontal cortex. We have previously shown that neuronal firing in the PL during the trace interval separating the cue and shock is required for trace cued fear memory formation, but whether this mnemonic signal is conveyed to the amygdala is unknown. Here we show in males that silencing PL activity during the trace interval reduces Arc protein in the basolateral amygdala (BLA) of trace-conditioned rats. Then, using pathway-specific optogenetic and chemogenetic silencing, we show a role for direct PL-BLA communication in trace cued fear learning under weak training conditions, but not standard training. These results suggest that PL input to the BLA may serve to promote cued learning when the cue-shock relationship is most ambiguous and that other trace fear circuitry can compensate for the loss of this connection with additional training. This also highlights the challenge to studying how emotional memories are formed and stored within a distributed network and suggests that the function of individual connections within such a network may best be determined using weak training conditions

Political trials and the suppression of popular radicalism in England, 1799-1820

This chapter examines the decision-making process between the Home Office and the government’s law officers in prosecuting individuals for sedition and treason in the period 1799–1820. The term state trial suggests a more centralised and government-led repression of popular radicalism than the process was in practice. Provincial reformers also faced the complex layers of their local justice system, which was more loyalist, committed to stamping out political radicalism. The trial of the “Thirty Eight” Manchester radicals in June 1812 demonstrates the mutable definitions of treason, sedition and processes of justice in the theatre of the court.Peer reviewe

Long Days Enhance Recognition Memory and Increase Insulin-like Growth Factor 2 in the Hippocampus

Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered hippocampal clock function and elevated transcription of Insulin-like Growth Factor2 (Igf2). Up-regulation of Igf2 occurred in tandem with suppression of its transcriptional repressor Wilm’s tumor1. Consistent with molecular de-repression of Igf2, IGF2 expression was increased in the hippocampus before and after memory training. Lastly, long days occluded IGF2-induced improvements in recognition memory. Collectively, these results suggest that light changes hippocampal clock function to alter memory, highlighting novel mechanisms that may contribute to the positive effects of light. Furthermore, this study provides insight into how the circadian clock can regulate hippocampus-dependent learning by controlling molecular processes required for memory consolidation

An Empirical Study of Topic Transition in Dialogue

Transitioning between topics is a natural component of human-human dialog. Although topic transition has been studied in dialogue for decades, only a handful of corpora based studies have been performed to investigate the subtleties of topic transitions. Thus, this study annotates 215 conversations from the switchboard corpus and investigates how variables such as length, number of topic transitions, topic transitions share by participants and turns/topic are related. This work presents an empirical study on topic transition in switchboard corpus followed by modelling topic transition with a precision of 83% for in-domain(id) test set and 82% on 10 out-of-domain}(ood) test set. It is envisioned that this work will help in emulating human-human like topic transition in open-domain dialog systems.Comment: 5 pages, 4 figures, 3 table

Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that regulates neuronal physiology and transcription through Gs/Gq-coupled receptors. Its actions within hypothalamic, limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition. Recently, elevated PACAP levels and genetic disruption of PAC1 receptor signaling in humans has been linked to maladaptive threat learning and pathological stress and fear in post-traumatic stress disorder (PTSD). PACAP is positioned to integrate stress and memory in PTSD for which memory of the traumatic experience is central to the disorder. However, PACAP’s role in memory has received comparatively less attention than its role in stress. In this review, we consider the evidence for PACAP-PAC1 receptor signaling in learning and plasticity, discuss emerging data on sex differences in PACAP signaling, and raise key questions for further study toward elucidating the contribution of PACAP to adaptive and maladaptive fear learning

Regional policy spillovers : the national impact of demand-side policy in an interregional model of the UK economy

UK regional policy has been advocated as a means of reducing regional disparities and stimulating national growth. However, there is limited understanding of the interregional and national effects of such a policy. This paper uses an interregional computable general equilibrium model to identify the national impact of a policy-induced regional demand shock under alternative labour market closures. Our simulation results suggest that regional policy operating solely on the demand side has significant national impacts. Furthermore, the effects on the nontarget region are particularly sensitive to the treatment of the regional labour market