Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma.

Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries

Postnatal maturation of somatostatin-expressing inhibitory cells in the somatosensory cortex of GIN mice

Postnatal inhibitory neuron development affects mammalian brain function, and failure of this maturation process may underlie pathological conditions such as epilepsy, schizophrenia, and depression. Furthermore, understanding how physiological properties of inhibitory neurons change throughout development is critical to understanding the role(s) these cells play in cortical processing. One subset of inhibitory neurons that may be affected during postnatal development is somatostatin-expressing (SOM) cells. A subset of these cells is labeled with green-fluorescent protein (GFP) in a line of mice known as the GFP-positive inhibitory neurons (GIN) line. Here, we studied how intrinsic electrophysiological properties of these cells changed in the somatosensory cortex of GIN mice between postnatal ages P11 and P32+. GIN cells were targeted for whole-cell current-clamp recordings and ranges of positive and negative current steps were presented to each cell. The results showed that as the neocortical circuitry matured during this critical time period multiple intrinsic and firing properties of GIN inhibitory neurons, as well as those of excitatory (regular-spiking [RS]) cells, were altered. Furthermore, these changes were such that the output of GIN cells, but not RS cells, increased over this developmental period. We quantified changes in excitability by examining the input–output relationship of both GIN and RS cells. We found that the firing frequency of GIN cells increased with age, while the rheobase current remained constant across development. This created a multiplicative increase in the input–output relationship of the GIN cells, leading to increases in gain with age. The input–output relationship of the RS cells, on the other hand, showed primarily a subtractive shift with age, but no substantial change in gain. These results suggest that as the neocortex matures, inhibition coming from GIN cells may become more influential in the circuit and play a greater role in the modulation of neocortical activity

NF-kB functions in synaptic signaling and behavior

Ca^(2+)-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-kB transcription factor by a pathway requiring the Ca^(2+)/calmodulin-dependent kinase CaMKII and local submembranous Ca^(2+) elevation. The p65:p50 NF-kB form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-kB. Activated NF-kB moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-kB nuclear translocation and gene activation

Prefrontal microcircuit underlies contextual learning after hippocampal loss

Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders

In need of mediation: The relation between syntax and information structure

This paper defends the view that syntax does not directly interact with information structure. Rather, information structure affects prosody, and only the latter has an interface with syntax. We illustrate this point by discussing scrambling, focus preposing, and topicalization. The position entertained here implies that syntax is not very informative when one wants to narrow down the interpretation of terms such as “focus”, “topic”, etc

The alpha1 subunit of the GABA(A) receptor modulates fear learning and plasticity in the lateral amygdala.

Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for example, depends on changes in excitatory transmission that occur following NMDA receptor activation and AMPA receptor modification in this region. The role of these and other glutamatergic mechanisms have been studied extensively in this circuit while relatively little is known about the contribution of inhibitory transmission. The current experiments addressed this issue by examining the role of the GABA(A) receptor subunit alpha1 in fear learning and plasticity. We first confirmed previous findings that the alpha1 subunit is highly expressed in the lateral nucleus of the amygdala. Consistent with this observation, genetic deletion of this subunit selectively enhanced plasticity in the lateral amygdala and increased auditory fear conditioning. Mice with selective deletion of alpha1 in excitatory cells did not exhibit enhanced learning. Finally, infusion of a alpha1 receptor antagonist into the lateral amygdala selectively impaired auditory fear learning. Together, these results suggest that inhibitory transmission mediated by alpha1-containing GABA(A) receptors plays a critical role in amygdala plasticity and fear learning