The Neurobiology of Fear Generalization

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models

Intrauterine Exposure to Maternal Stress Alters Bdnf IV DNA Methylation and Telomere Length in the Brain of Adult Rat Offspring

DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could contribute to the long-term effects of intrauterine exposure to maternal stress on offspring behavioral outcomes. Here, we measured methylation of Brain-derived neurotrophic factor (Bdnf), a gene important in development and plasticity, and telomere length in the brains of adult rat male and female offspring whose mothers were exposed to unpredictable and variable stressors throughout gestation. Males exposed to prenatal stress had greater methylation (Bdnf IV) in the medial prefrontal cortex (mPFC) compared to non-stressed controls. Further, prenatally-stressed males had shorter telomeres than controls in the mPFC. This study provides the first evidence in a rodent model of an association between prenatal stress exposure and subsequent shorter brain telomere length. Together findings indicate a long-term impact of prenatal stress on DNA methylation and telomere biology with relevance for behavioral and health outcomes, and contribute to a growing literature linking stress to intergenerational epigenetic alterations and changes in telomere length

Sex Differences in Remote Contextual Fear Generalization in Mice

The generalization of fear is adaptive in that it allows an animal to respond appropriately to novel threats that are not identical to previous experiences. In contrast, the overgeneralization of fear is maladaptive and is a hallmark of post-traumatic stress disorder (PTSD), a psychiatric illness that is characterized by chronic symptomatology and a higher incidence in women compared to men. Therefore, understanding the neural basis of fear generalization at remote time-points in female animals is of particular translational relevance. However, our understanding of the neurobiology of fear generalization is largely restricted to studies employing male mice and focusing on recent time-points (i.e., within 24–48 h following conditioning). To address these limitations, we examined how male and female mice generalize contextual fear at remote time intervals (i.e., 3 weeks after conditioning). In agreement with earlier studies of fear generalization at proximal time-points, we find that the test order of training and generalization contexts is a critical determinant of generalization and context discrimination, particularly for female mice. However, tactile elements that are present during fear conditioning are more salient for male mice. Our study highlights long-term sex differences in defensive behavior between male and female mice and may provide insight into sex differences in the processing and retrieval of remote fear memory observed in humans

Thermoreversible gelation of poly(vinylidene flouride) in diethyl adipate: a concerted mechanism

Poly(vinylidene flouride) (PVF2) gels in diethyl adipate (DEA) with fibrillar morphology. The gels are transparent. The Wide-angle X-ray scattering pattern and FT-IR spectra of the gel indicate the presence of solvated a-phase PVF2crystallites in the gel. The intensities of the X-ray diffraction peaks of the gel are mostly different than those of the melt-crystallized sample. The plots of enthalpy of gel fusion and enthalpy of gel formation with a weight fraction of PVF2 (WPVF2) indicate a positive deviation from linearity. Analysis of these results indicates polymer-solvent complex formation in the molar ratio of 1:2 for the DEA and PVF2 repeating unit, respectively. The phase diagram also supports polymer-solvent complex formation with an incongruent melting point. The gelation kinetics is studied by the test tube tilting method. Analysis of the concentration function of the gelation rate supports the theory that this gelation process obeys the three-dimensional percolation mechanism. The temperature coefficient analysis is done both by the Flory and Weaver theory of coil-to-helix transtion and by the growth rate theory of fibrillar crystallization extended to the polymer-diluent system. A comparison of energy barrier values of both the processes indicates that the gelation is a concerted process of conformational ordering and crystallization

Thermoreversible gelation of poly(vinylidene fluoride) in diesters: influence of intermittent length on morphology and thermodynamics of gelation

Poly(vinylidene fluoride) (PVF2) produces thermoreversible gels in diesters. By variation of the number of intermittent carbon atoms (n = 0-7) of the diesters, the physical properties of the gels are studied. The morphology of the PVF2/diethyl oxalate (DEO) gel is spheroidal, but the morphology of PVF2-diethyl malonate (DEM) gel is a mixture of both spheroidal and fibrillar. The PVF2/diethyl succinate (DES), PVF2/diethyl gluterate (DEG), PVF2/diethyl pimelate (DEP), and PVF2/diethyl azelate (DEAZ) gels are "fibrillar-like" as evidenced from scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The X-ray and solvent subtracted FT-IR spectra indicate the presence of α-polymorph PVF2 in all the gels. The enthalpy of gel formation and the enthalpy of gel fusion, measured from differential scanning calorimetry (DSC), show linear plot with PVF2concentration for PVF2-DEO gels but others exhibit positive deviation from linearity. From the deviation vs PVF2 weight fraction (WPVF2) plot, the compositions of the polymer solvent complexes are found to be 1:3, 1:2, 1:4, 1:4, and 1:3 in the molar ratio of the diester and PVF2 repeating unit, for gels in DEM, DES, DEG, DEP, and DEAZ, respectively. The phase diagrams of PVF2-DEM, PVF2-DES, and PVF2-DEP gels indicate polymer-solvent compound formation with a singular point while those of the PVF2-DEG and PVF2-DEAZ gels indicate compound formation with an incongruent melting point. The polymer solvent compound formation is also studied by molecular mechanics calculations using MMX program. The pairs of α-PVF2 and diester molecules with appropriate conformation to match the composition of the complex are energetically minimized. The distances between the >CF2 group and the carbonyl oxygen are lower than the summation of their van der Waals radii for all the diesters. The discrepancy between molecular modeling and morphology of the PVF2-DEO gels and the borderline morphology of PVF2-DEM gels have been explained from molecular mobility of the solvent and enthalpy of complexation (ΔHc). The gel melting temperature and gelation temperature increases with increase in intermittent length (n) for a particular PVF2concentration. Also, ΔHc increases with "n", and this indicates that the intermittent length of diesters has both enthalpic and entropic contribution on gel behavior of PVF2

An equilibrium study on the distribution of structural defects between the lamellar and amorphous portions of poly(vinylidene fluoride) and (vinylidene fluoride-tetra fluoro ethylene) copolymer crystals

Samples of poly(vinylidene fluoride) (PVF2) and (vinylidene fluoride-tetra fluoroethylene) (VF2-VF4) copolymer were etched with a chromium-based etching reagent. The etching rate was lower for the VF2-VF4 copolymer samples than for the PVF2 samples. The melting point and enthalpy of fusion increased with increased etching time of the etched specimen. This was also true for the melt-quenched (etched) samples, whose values were always lower than those obtained from the direct run of the etched samples. The scanning electron micrographs of specimens etched for 24 h indicated that only the amorphous portion was etched without affecting the crystalline lamella. The sequence distribution of the PVF2 and VF2-VF4 copolymer crystals were determined by 19F NMR measurements of the samples and their etched species. The observed probabilities (Pobs), calculated from the integrated area of the NMR peaks, indicated that the crystalline lamella had a more oriented chain structure than that of the amorphous overlayer portion. The head-to-head defects calculated from the aforementioned sequence analysis indicated a greater propensity in the amorphous portion than in the crystalline lamella. The equilibrium constant (K) for the distribution of defects between the lamella and amorphous portion of the crystal varied from 0.7 to 0.9. It was higher at a higher quenching rate of the crystallization, and in the isothermal crystallization, it also had a substantially high value, indicating the equilibrium inclusion of defects in the crystal. The distribution constant increased with an increase in the defect content in the chain and decreased with an increase in the defect size. The sequence distribution data, analyzed through a suitable melting-point depression equation, indicated a defect energy of 2.25 kcal/mol for the -phase PVF2 crystals and 0.68 kcal/mol for the β-phase VF2-VF4 copolymer