Fear of cancer recurrence and change in hair cortisol concentrations in partners of breast cancer survivors.

PURPOSE: Partners of breast cancer (BC) survivors report high rates of psychological distress including fear of cancer recurrence (FCR). Research suggests that partners may have poorer physical health outcomes than the general population, but little research has examined the physiological biomarkers by which distress may impact partner health outcomes. The current study examined the associations between FCR and changes in hair cortisol among BC partners. METHODS: Male partners (N = 73) of early-stage BC survivors provided hair samples during two visits, one after completion of survivors' adjuvant treatment (T1) and again 6 months later (T2). Two subscales from the Fear of Cancer Recurrence Inventory and one subscale from the Concerns about Recurrence Scale comprised a latent FCR factor at T1. A latent change score model was used to examine change in cortisol as a function of FCR. RESULTS: Partners were on average 59.65 years of age (SD = 10.53) and non-Hispanic White (83%). Latent FCR at T1 was positively associated (b = 0.08, SE = 0.03, p = .004, standardized ß = .45) with change in latent hair cortisol from T1 to T2. CONCLUSIONS: Results indicated that greater FCR was associated with increases in hair cortisol in the months following adjuvant treatment. This is one of the first studies to examine the physiological correlates of FCR that may impact health outcomes in BC partners. IMPLICATIONS FOR CANCER SURVIVORS: Findings highlight the need for further research into the relationship between FCR and its physiological consequences. Interventions to address partner FCR are needed and may aid in improving downstream physical health outcomes.

Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory.

The hippocampus contains a diverse array of inhibitory interneurons that gate information flow through local cortico-hippocampal circuits to regulate memory storage. Although most studies of interneurons have focused on their role in fast synaptic inhibition mediated by GABA release, different classes of interneurons express unique sets of neuropeptides, many of which have been shown to exert powerful effects on neuronal function and memory when applied pharmacologically. However, relatively little is known about whether and how release of endogenous neuropeptides from inhibitory cells contributes to their behavioral role in regulating memory formation. Here we report that vasoactive intestinal peptide (VIP)-expressing interneurons participate in social memory storage by enhancing information transfer from hippocampal CA3 pyramidal neurons to CA2 pyramidal neurons. Notably, this action depends on release of the neuropeptide enkephalin from VIP neurons, causing long-term depression of feedforward inhibition onto CA2 pyramidal cells. Moreover, VIP neuron activity in the CA2 region is increased selectively during exploration of a novel conspecific. Our findings, thus, enhance our appreciation of how GABAergic neurons can regulate synaptic plasticity and mnemonic behavior by demonstrating that such actions can be mediated by release of a specific neuropeptide, rather than through classic fast inhibitory transmission.

Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

A circuit from hippocampal CA2 to lateral septum disinhibits social aggression.

Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression.

Immediate early gene and neuropeptide expression following exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT).

The immediate early gene c-fos and a number of neuropeptides have been widely used to help delineate the neural circuitry of innate fear to predator odors. The present study used in situ hybridization techniques to examine the expression of the immediate early gene transcription factors c-fos and egr-1, and the neuropeptides corticotropin-releasing hormone (crh) and enkephalin (enk) following exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). Rats were exposed to water (H2O), TMT, or the irritating odor butyric acid (BA) and freezing was used to measure fear behavior. Changes in gene expression were analyzed in the medial prefrontal cortex (mPFC), the bed nucleus of the stria terminalis (BNST), paraventricular nucleus of the hypothalamus (PVN), and central nucleus of the amygdala (CeA). Animals froze more to TMT than BA and H2O, and more to BA than H2O. Compared to H2O and BA, c-fos and egr-1 were elevated within the BNST, PVN, and CeA in rats exposed to TMT, but not the mPFC. Crh was also elevated in rats exposed to TMT within the CeA and PVN, but not the BNST or mPFC. Enk was elevated within the PVN in TMT and BA exposed rats compared to H2O exposure. These data indicate that exposure to the predator odor TMT induces similar expression patterns for c-fos and egr-1, but different patterns for crh and enk, with partial overlap of the immediate-early genes and neuropeptides within specific brain regions.