The precise nature of the engram, the physical substrate of memory, remains uncertain. Here, it is reported that RNA extracted from the central nervous system of Aplysia given long-term sensitization (LTS) training induced sensitization when injected into untrained animals; furthermore, the RNA-induced sensitization, like training-induced sensitization, required DNA methylation. In cellular experiments, treatment with RNA extracted from trained animals was found to increase excitability in sensory neurons, but not in motor neurons, dissociated from naïve animals. Thus, the behavioral, and a subset of the cellular, modifications characteristic of a form of nonassociative long-term memory (LTM) in Aplysia can be transferred by RNA. These results indicate that RNA is sufficient to generate an engram for LTS in Aplysia and are consistent with the hypothesis that RNA-induced epigenetic changes underlie memory storage in Aplysia.
The robustness of the visual system lies in its ability to perceive degraded images. This is achieved through interacting bottom-up, recurrent, and top-down pathways that process the visual input in concordance with stored prior information. The interaction mechanism by which they integrate visual input and prior information is still enigmatic. We present a new approach using deep neural network (DNN) representation to reveal the effects of such integration on degraded visual inputs. We transformed measured human brain activity resulting from viewing blurred images to the hierarchical representation space derived from a feedforward DNN. Transformed representations were found to veer toward the original nonblurred image and away from the blurred stimulus image. This indicated deblurring or sharpening in the neural representation, and possibly in our perception. We anticipate these results will help unravel the interplay mechanism between bottom-up, recurrent, and top-down pathways, leading to more comprehensive models of vision.
Uncovering the neural dynamics of facial identity processing along with its representational basis outlines a major endeavor in the study of visual processing. To this end, here, we record human electroencephalography (EEG) data associated with viewing face stimuli; then, we exploit spatiotemporal EEG information to determine the neural correlates of facial identity representations and to reconstruct the appearance of the corresponding stimuli. Our findings indicate that multiple temporal intervals support: facial identity classification, face space estimation, visual feature extraction and image reconstruction. In particular, we note that both classification and reconstruction accuracy peak in the proximity of the N170 component. Further, aggregate data from a larger interval (50-650 ms after stimulus onset) support robust reconstruction results, consistent with the availability of distinct visual information over time. Thus, theoretically, our findings shed light on the time course of face processing while, methodologically, they demonstrate the feasibility of EEG-based image reconstruction.
Cognitive reserve, the brain’s capacity to draw on enriching experiences during youth, is believed to protect against memory loss associated with a decline in hippocampal function, as seen in normal aging and neurodegenerative disease. Adult neurogenesis has been suggested as a specific mechanism involved in cognitive (or neurogenic) reserve. The first objective of this study was to compare learning-related neuronal activity in adult-born versus developmentally born hippocampal neurons in juvenile male rats that had engaged in extensive running activity during early development or reared in a standard laboratory environment. The second objective was to investigate the long-term effect of exercise in rats on learning and memory of a contextual fear (CF) response later in adulthood. These aims address the important question as to whether exercise in early life is sufficient to build a reserve that protects against the process of cognitive aging. The results reveal a long-term effect of early running on adult-born dentate granule neurons and a special role for adult-born neurons in contextual memory, in a manner that is consistent with the neurogenic reserve hypothesis.
Economic decisions arise from evaluation of alternative actions in contexts of motivation and memory. In the predatory sea-slugPleurobranchaeathe economic decisions of foraging are found to occur by the workings of a simple, affectively controlled homeostat with learning abilities. Here, the neuronal circuit relations for approach-avoidance choice ofPleurobranchaeaare expressed and tested in the foraging simulation Cyberslug. Choice is organized around appetitive state as a moment-to-moment integration of sensation, motivation (satiation/hunger), and memory. Appetitive state controls a switch for approach vs. avoidance turn responses to sensation. Sensory stimuli are separately integrated for incentive value into appetitive state, and for prey location (stimulus place) into mapping motor response. Learning interacts with satiation to regulate prey choice affectively. The virtual predator realistically reproduces the decisions of the real one in varying circumstances and satisfies optimal foraging criteria. The basic relations are open to experimental embellishment toward enhanced neural and behavioral complexity in simulation, as was the ancestral bilaterian nervous system in evolution.
Neuroscience research has historically ignored female animals. This neglect comes in two general forms. The first is sex bias, defined as favoring one sex over another; in this case, male over female. The second is sex omission, which is the lack of reporting sex. The recognition of this phenomenon has generated fierce debate across the sciences. Here we test whether sex bias and omission are still present in the neuroscience literature, whether studies employing both males and females neglect sex as an experimental variable, and whether sex bias and omission differs between animal models and journals. To accomplish this, we analyzed the largest-ever number of neuroscience articles for sex bias and omission: 6636 articles using mice or rats in 6 journals published from 2010 to 2014. Sex omission is declining, as increasing numbers of articles report sex. Sex bias remains present, as increasing numbers of articles report the sole use of males. Articles using both males and females are also increasing, but few report assessing sex as an experimental variable. Sex bias and omission varies substantially by animal model and journal. These findings are essential for understanding the complex status of sex bias and omission in neuroscience research and may inform effective decisions regarding policy action.
When intentionally pushed or insulted, one can either flee from the provoker or retaliate. The implementation of such fight-or-flight decisions is a central aspect in the genesis and evolution of aggression episodes, yet it is usually investigated only indirectly or in nonsocial situations. In the present fMRI study, we aimed to distinguish brain regions associated with aggressive and avoidant responses to interpersonal provocation in humans. Participants (thirty-six healthy young women) could either avoid or face a highly (HP) and a lowly (LP) provoking opponent in a competitive reaction time task: the fight-or-escape (FOE) paradigm. Subjects avoided the HP more often, but retaliated when facing her. Moreover, they chose to fight the HP more quickly, and showed increased heart rate (HR) right before confronting her. Orbitofrontal cortex (OFC) and sensorimotor cortex were more active when participants decided to fight, whereas the mentalizing network was engaged when deciding to avoid. Importantly, avoiding the HP relative to the LP was associated with both higher activation in the right basolateral amygdala and lower relative activity in several mentalizing regions [e.g., medial and inferior frontal gyrus (IFG), temporal-parietal junction (TPJ)]. These results suggest that avoidant responses to provocation might result from heightened threat anticipation and are associated with reduced perspective taking. Furthermore, our study helps to reconcile conflicting findings on the role of the mentalizing network, the amygdala, and the OFC in aggression.
Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers. Here, we report the identification and characterization of antibodies that reliably detect several human GRNs by immunoblot and immunocytochemistry. Using these tools, we find that endogenous GRNs are present within multiple cell lines and are constitutively produced. Further, extracellular PGRN is endocytosed and rapidly processed into stable GRNs within lysosomes. Processing of PGRN into GRNs is conserved between humans and mice and is modulated by sortilin expression and mediated by cysteine proteases (i.e. cathpesin L). Induced lysosome dysfunction caused by alkalizing agents or increased expression of transmembrane protein 106B (TMEM106B) inhibit processing of PGRN into GRNs. Finally, we find that multiple GRNs are haploinsufficient in primary fibroblasts and cortical brain tissue from FTD-GRN patients. Taken together, our findings raise the interesting possibility that GRNs carry out critical lysosomal functions and that loss of GRNs should be explored as an initiating factor in lysosomal dysfunction and neurodegeneration caused by GRN mutations.
Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract.
In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of Nlgn3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other’s behavior. We have found that, when raised together, male Nlgn3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male Nlgn3 knockout mice correlated with an increase in their anxiety. Re-expression of Nlgn3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of Nlgn3 knockout mice has a direct and measurable impact on wild-type animals' behavior. Finally, we showed that, unlike male mice, female mice lacking Nlgn3 were insensitive to their peers' behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking Nlgn3, being more influential in males than females.