The PFC, through its high degree of interconnectivity with cortical and subcortical brain areas, mediates cognitive and emotional processes in support of adaptive behaviors. This includes the ...formation of fear memories when the anticipation of threat demands learning about temporal or contextual cues, as in trace fear conditioning. In this variant of fear learning, the association of a cue and shock across an empty trace interval of several seconds requires sustained cue-elicited firing in the prelimbic cortex (PL). However, it is unknown how and when distinct PL afferents contribute to different associative components of memory. Among the prominent inputs to PL, the hippocampus shares with PL a role in both working memory and contextual processing. Here we tested the necessity of direct hippocampal input to the PL for the acquisition of trace-cued fear memory and the simultaneously acquired contextual fear association. Optogenetic silencing of ventral hippocampal (VH) terminals in the PL of adult male Long-Evans rats selectively during paired trials revealed that direct communication between the VH and PL during training is necessary for contextual fear memory, but not for trace-cued fear acquisition. The pattern of the contextual memory deficit and the disruption of local PL firing during optogenetic silencing of VH-PL suggest that the VH continuously updates the PL with the current contextual state of the animal, which, when disrupted during memory acquisition, is detrimental to the subsequent rapid retrieval of aversive contextual associations.
Learning to anticipate threat from available contextual and discrete cues is crucial for survival. The prelimbic cortex is required for forming fear memories when temporal or contextual complexity is involved, as in trace fear conditioning. However, the respective contribution of distinct prelimbic afferents to the temporal and contextual components of memory is not known. We report that direct input from the ventral hippocampus enables the formation of the contextual, but not trace-cued, fear memory necessary for the subsequent rapid expression of a fear response. This finding dissociates the contextual and working-memory contributions of prelimbic cortex to the formation of a fear memory and demonstrates the crucial role for hippocampal input in contextual fear learning.
Adaptive social behavior requires transmission and reception of salient social information. Impairment of this reciprocity is a cardinal symptom of autism. The amygdala is a critical mediator of ...social behavior and is implicated in social symptoms of autism. Here we found that a specific amygdala circuit, from the lateral nucleus to the medial nucleus (LA-MeA), is required for using social cues to learn about environmental cues that signal imminent threats. Disruption of the LA-MeA circuit impaired valuation of these environmental cues and subsequent ability to use a cue to guide behavior. Rats with impaired social guidance of behavior due to knockout of Nrxn1, an analog of autism-associated gene NRXN, exhibited marked LA-MeA deficits. Chemogenetic activation of this circuit reversed these impaired social behaviors. These findings identify an amygdala circuit required to guide emotional responses to socially significant cues and identify an exploratory target for disorders associated with social impairments.
•Ventral hippocampal neurons in both sexes robustly encode the shock UCS.•Ventral hippocampal neurons show only modest encoding of the CS and no encoding of the trace interval.•Ventral hippocampal ...shock-evoked activity modulates the expression of learned fear at test in a sex-specific manner.
The hippocampus is crucial for associative fear learning when the anticipation of threat requires temporal or contextual binding of predictive stimuli as in trace and contextual fear conditioning. Compared with the dorsal hippocampus, far less is known about the contribution of the ventral hippocampus to fear learning. The ventral hippocampus, which is highly interconnected with defensive and emotional networks, has a prominent role in both innate and learned affective behaviors including anxiety, fear, and reward. Lesions or temporary inactivation of the ventral hippocampus impair both cued and contextual fear learning, but whether the ventral hippocampal role in learning is driven by affective processing, associative encoding, or both is not clear. Here, we used trace fear conditioning in mixed sex cohorts to assess the contribution of shock-encoding to the acquisition of cued and contextual fear memories. Trace conditioning requires subjects to associate an auditory conditional stimulus (CS) with a shock unconditional stimulus (UCS) that are separated in time by a 20-s trace interval. We first recorded neuronal activity in the ventral hippocampus during trace fear conditioning and found that ventral CA1 predominantly encoded the shock reinforcer. Potentiated firing to the CS was evident at testing, but no encoding of the trace interval was observed. We then tested the necessity of shock encoding for conditional fear acquisition by optogenetically silencing ventral hippocampal activity during the UCS on each trial of training. Contrary to our predictions, preventing hippocampal shock-evoked firing did not impair associative fear. Instead, it led to a more prolonged expression of CS freezing across test trials, an effect observed in males, but not females. Contextual fear learning was largely intact, although a subset of animals in each sex were differentially affected by shock-silencing. Taken together, the results show that shock encoding in the ventral hippocampus modulates the expression of learned fear in a sex-specific manner.
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.
Many smokers report attempting to quit each year, yet most relapse, in part due to exposure to smoking-related cues. It is hypothesized that extinction of the cue-drug association could be ...facilitated through random nicotine delivery (RND), thus making it easier for smokers to quit. The current study aimed to evaluate the effects of RND on smoking cessation-related outcomes including cigarettes per day (CPD) and exhaled carbon monoxide (CO).
Participants were current smokers (>9 CPD) interested in quitting. Novel trans-mucosal, orally dissolving nicotine films, developed by Bionex Pharmaceuticals, were used in the study. The pharmacokinetic profile of these films was assessed in single (Experiment 1) and multiple-dose (Experiment 2) administrations prior to the smoking cessation study (Experiment 3). In Experiment 3, participants were randomized 1:1:1 to recieve 4 nicotine films per day of either: placebo delivery (0 mg), steady-state delivery (2 mg), or random nicotine delivery (RND) (0 mg or 4 mg). After two weeks, participants were advised to quit (target quit date, TQD) and were followed up 4 weeks later to collect CPD and CO and to measure dependence (Penn State Cigarette Dependence Index; PSCDI) and craving (Questionnaire of Smoking Urges; QSU-Brief). Means and frequencies were used to describe the data and repeated measures ANOVA was used to determine differences between groups.
The pharmacokinetic studies (Experiment 1 and 2) demonstrated that the films designed for this study delivered nicotine as expected, with the 4 mg film delivering a nicotine boost of approximately 12.4 ng/mL across both the single and the multiple dose administration studies. The films reduced craving for a cigarette and were well-tolerated, overall, and caused no changes in blood pressure or heart rate. Using these films in the cessation study (Experiment 3) (n = 45), there was a significant overall reduction in cigarettes smoked per day (CPD) and in exhaled CO, with no significant differences across groups (placebo, steady-state, RND). In addition, there were no group differences in dependence or craving. Adverse events included heartburn, hiccups, nausea, and to a lesser extent, vomiting and anxiety and there were no differences across groups.
Overall, this pilot study found that RND via orally dissolving films was feasible and well tolerated by participants. However, RND participants did not experience a greater reduction in self-reported CPD and exhaled CO, compared with participants in the steady-state and placebo delivery groups. Future studies to evaluate optimal RND parameters with larger sample sizes are needed to fully understand the effect of RND on smoking cessation-related outcomes.
Drug exposure results in structural and functional changes in brain regions that regulate reward and these changes may underlie the persistence of compulsive drug seeking and relapse. Neurotrophic ...factors, such as basic fibroblast growth factor (bFGF or FGF2), are necessary for neuronal survival, growth, and differentiation, and may contribute to these drug-induced changes. Following cocaine exposure, bFGF is increased in addiction-related brain regions, including the infralimbic medial prefrontal cortex (IL-mPFC). The IL-mPFC is necessary for extinction, but whether drug-induced overexpression of bFGF in this region affects extinction of drug seeking is unknown. Thus, we determined whether blocking bFGF in IL-mPFC would facilitate extinction following cocaine self-administration. Rats were trained to lever press for intravenous infusions of cocaine before extinction. Blocking bFGF in IL-mPFC before four extinction sessions resulted in facilitated extinction. In contrast, blocking bFGF alone was not sufficient to facilitate extinction, as blocking bFGF and returning rats to their home cage had no effect on subsequent extinction. Furthermore, bFGF protein expression increased in IL-mPFC following cocaine self-administration, an effect reversed by extinction. These results suggest that cocaine-induced overexpression of bFGF inhibits extinction, as blocking bFGF during extinction permits rapid extinction. Therefore, targeted reductions in bFGF during therapeutic interventions could enhance treatment outcomes for addiction.
•Prelimbic muscarinic signaling is required for trace and contextual fear memories.•The estrous cycle gates the fear memory-impairing effects of scopolamine in females.•A higher dose of scopolamine ...is required to impair fear memory in females than males.•Scopolamine suppresses subsequent drug-free acquisition to the originally trained cue.
The association of a sensory cue and an aversive footshock that are separated in time, as in trace fear conditioning, requires persistent activity in prelimbic cortex during the cue-shock interval. The activation of muscarinic acetylcholine receptors has been shown to facilitate persistent firing of cortical cells in response to brief stimulation, and muscarinic antagonists in the prefrontal cortex impair working memory. It is unknown, however, if the acquisition of associative trace fear conditioning is dependent on muscarinic signaling in the prefrontal cortex. Here, we delivered the muscarinic receptor antagonist scopolamine to the prelimbic cortex of rats prior to trace fear conditioning and tested their memories of the cue and training context the following day. The effect of scopolamine on working memory performance was also tested using a spatial delayed non-match to sample task. Male and female subjects were included to examine potential sex differences in the modulation of memory formation, as we have previously observed for pituitary adenylate cyclase-activating polypeptide signaling in the prefrontal cortex (Kirry et al., 2018). We found that pre-training administration of intra-prelimbic scopolamine impaired the formation of cued and contextual fear memories in males, but not females at a dose that impairs spatial working memory in both sexes. Fear memory formation in females was impaired by a higher dose of scopolamine and this impairment was gated by estrous cycle stage: scopolamine failed to impair memory in rats in the diestrus or proestrus stages of the estrous cycle. These findings add to the growing body of evidence that the prefrontal cortex is sexually dimorphic in learning and memory and additionally suggest that males and females differentially engage prefrontal neuromodulatory systems in support of learning.
Kappa counterconditioning of cocaine cues Mantsch, John R; Twining, Robert C
Neuropsychopharmacology (New York, N.Y.),
06/2018, Letnik:
43, Številka:
7
Journal Article
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.
•Prefrontal PAC1 receptor signaling contributes to the strength of cued, but not contextual, fear memory.•The effects of blocking prefrontal PAC1 receptor signaling are specific to females.•Females exhibit greater PAC1 receptor mRNA expression compared with males.•Prefrontal PAC1 receptor signaling is a potential neurobiological substrate of PTSD in women.
The importance of neuronal glutamate to synaptic transmission throughout the brain illustrates the immense therapeutic potential and safety risks of targeting this system. Astrocytes also release ...glutamate, the clinical relevance of which is unknown as the range of brain functions reliant on signaling from these cells hasn't been fully established. Here, we investigated system xc- (Sxc), which is a glutamate release mechanism with an
rodent expression pattern that is restricted to astrocytes. As most animals do not express Sxc, we first compared the expression and sequence of the obligatory Sxc subunit xCT among major classes of vertebrate species. We found xCT to be ubiquitously expressed and under significant negative selective pressure. Hence, Sxc likely confers important advantages to vertebrate brain function that may promote biological fitness. Next, we assessed brain function in male genetically modified rats (
) created to eliminate Sxc activity. Unlike other glutamatergic mechanisms, eliminating Sxc activity was not lethal and didn't alter growth patterns, telemetry measures of basic health, locomotor activity, or behaviors reliant on simple learning. However,
rats exhibited deficits in tasks used to assess cognitive behavioral control. In a pavlovian conditioned approach,
rats approached a food-predicted cue more frequently than WT rats, even when this response was punished. In attentional set shifting,
rats displayed cognitive inflexibility because of an increased frequency of perseverative errors.
rats also displayed heightened cocaine-primed drug seeking. Hence, a loss of Sxc-activity appears to weaken control over nonreinforced or negative-outcome behaviors without altering basic brain function.
Glutamate is essential to synaptic activity throughout the brain, which illustrates immense therapeutic potential and risk. Notably, glutamatergic mechanisms are expressed by most types of brain cells. Hence, glutamate likely encodes multiple forms of intercellular signaling. Here, we hypothesized that the selective manipulation of astrocyte to neuron signaling would alter cognition without producing widespread brain impairments. First, we eliminated activity of the astrocytic glutamate release mechanism, Sxc, in rat. This impaired cognitive flexibility and increased expression of perseverative, maladaptive behaviors. Notably, eliminating Sxc activity did not alter metrics of health or noncognitive brain function. These data add to recent evidence that the brain expresses cognition-specific molecular mechanisms that could lead to highly precise, safe medications for impaired cognition.
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