Biology subjects

Likhtik, E.

Publications and source records attributed to Likhtik, E..

7 recordsLinked to original sources

bioRxiv2025

PV - Oligodendrocyte Interactions in the Infralimbic Cortex Promote Extracellular Plasticity after Safety Learning

Safety learning is mediated by the infralimbic region (IL) of the medial prefrontal cortex, but its cellular mechanisms are poorly understood. Here we show that safety learning improves cognitive flexibility in the long-term, which is associated with recruitment of oligodendrocyte progenitor cells to a satellite position at parvalbumin (PV) interneurons in the IL and their maturation into oligodendrocytes (OLs), as well as a decrease in perineuronal nets (PNNs) surrounding PVs paired with satellite OLs. Using scRNA transcriptomic data mining, we demonstrate that immature OLs primarily express PNN assembly genes, whereas mature OLs express PNN degradation enzymes. We then demonstrate that inhibiting IL PVs during safety learning prevents safety-induced cognitive flexibility, satellite OL maturation, and PNN degradation around IL PV. Thus, we propose that safety learning drives a novel form of neuro-glial plasticity that helps degrade PNNs around PV interneurons via OL recruitment and maturation, thereby shaping IL long-term activity.

neuroscience↗

bioRxiv2024

Social Isolation During Adolescence Differentially Affects Spatial Learning in Adult Male and Female Mice

Social isolation is a risk factor for cognitive impairment. Adolescents may be particularly vulnerable to these effects, because they are in a critical period of development marked by significant physical, hormonal, and social changes. However, it is unclear if the effects of social isolation on learning and memory are similar in both sexes or if they persist into adulthood after a period of recovery. We socially isolated male and female 129Sv/Ev mice throughout adolescence (post-natal days 29-56), provided a 2-week re-socialization recovery period, and then tested spatial learning and cognitive flexibility in the active place avoidance task. After behavioral testing, mice were injected with 5-bromo-2-deoxyuridine (BrdU) so that lasting effects of social isolation on cell proliferation in the dentate gyrus could be examined. We found that in males, isolation led to a modest impairment in the rate of initial spatial learning, whereas in females, initial learning was unaffected. However, when the location of the shock zone was switched during the conflict variant of the task, cognitive flexibility was impaired in females only. Similarly, social isolation reduced cell proliferation in the ventral dentate gyrus only in females. Together, these findings indicate that social isolation during adolescence differentially impairs spatial processing in males and females, with effects that persist into adulthood.

neuroscience↗

bioRxiv2024

Infralimbic projections to the basal forebrain mediate extinction learning

Fear extinction learning and retrieval are critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), the contribution of the IL to extinction learning is not well-understood. Given the strong projection from the IL to the basal forebrain (BF), a center of attentional processing, we investigated whether this pathway participates in extinction, and compared it to the IL-BLA pathway. Using retrograde tracing, we first demonstrate that projections from the IL to the BF originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling of the immediate early gene cFos, we show increased activity of the L5 IL-BF pathway during extinction learning and increased activity of the L2/3 IL-BLA pathway during extinction retrieval. Our in vitro recordings demonstrate that neurons in the IL-BF pathway become more excitable towards the end of extinction learning, but less excitable during extinction retrieval. Finally, using optogenetics we show that inactivation of the IL-BF pathway impairs extinction learning, leaving retrieval intact. We propose that the IL acts as a switchboard operator during extinction, with increased L5 IL-BF communication during learning and increased L2/3 IL-BLA communication during retrieval. Anxiety and stress-related changes in IL physiology could affect one or multiple lines of communication, impairing different aspects of extinction. Significance StatementExtinction of conditioned fear is a widely used behavioral approach to diminish fear, with projections from infralimbic prefrontal cortex to the amygdala known for mediating extinction memory retrieval. However, less is known about infralimbic pathways involved in extinction learning. We use neuroanatomical tracing, behavior, slice recordings, and circuit manipulation to show that infralimbic output to the basal forebrain, an attention processing center, is denser than to the amygdala, and is active during extinction learning rather than retrieval. Neurons in the infralimbic-basal forebrain pathway become more excitable as extinction learning progresses, and then less excitable during extinction retrieval. Moreover, inhibiting this pathway impairs extinction learning. Our findings identify different lines of communication the infralimbic cortex uses for extinction learning and retrieval.

neuroscience↗

bioRxiv2024

Chronic Social Defeat Stress Gives Rise to Social Avoidance Through Fear Learning

Chronic social defeat stress (CSDS), a widely used rodent model of stress, reliably leads to decreased social interaction in stress susceptible animals. Here, we investigate a role for fear learning in this response using 129Sv/Ev mice, a strain that is more vulnerable to CSDS than the commonly used C57BL/6 strain. We first demonstrate that defeated 129Sv/Ev mice avoid a CD-1 mouse, but not a conspecific, indicating that motivation to socialize is intact in this strain. CD-1 avoidance is characterized by approach behavior that results in running in the opposite direction, activity that is consistent with a threat response. We next test whether CD-1 avoidance is subject to the same behavioral changes found in traditional models of Pavlovian fear conditioning. We find that associative learning occurs across 10 days CSDS, with defeated mice learning to associate the color of the CD-1 coat with threat. This leads to the gradual acquisition of avoidance behavior, a conditioned response that can be extinguished with 7 days of repeated social interaction testing (5 tests/day). Pairing a CD-1 with a tone leads to second-order conditioning, resulting in avoidance of an enclosure without a social target. Finally, we show that social interaction with a conspecific is a highly variable response in defeated mice that may reflect individual differences in generalization of fear to other social targets. Our data indicate that fear conditioning to a social target is a key component of CSDS, implicating the involvement of fear circuits in social avoidance.

animal behavior and cognition↗

bioRxiv2023

Serotonergic modulation of the BNST-CeA circuit promotes sex differences in fear learning

Post-traumatic stress disorder (PTSD) is characterized by intense fear memory formation and is diagnosed more often in women than men. Here, we show that serotonin differentially affects fear learning and communication in the extended amygdala of male and female mice. Females showed higher sensitivity to the effects of pharmacologically increasing serotonin during auditory fear conditioning, which enhanced fear memory recall in both sexes. Optogenetic stimulation of dorsal raphe terminals in the anterior dorsal bed nucleus of the stria terminalis (adBNST) during fear conditioning increased c-Fos expression in the BNST and central nucleus of the amygdala (CeA), and enhanced fear memory recall via activation of adBNST 5-HT2C receptors in females only. Likewise, in females only, serotonin stimulation during learning enhanced adBNST-CeA high gamma (90-140Hz) synchrony and adBNST-to-CeA communication in high gamma during fear memory recall. We conclude that sex differences in the raphe-BNST-CeA circuit may increase risk of PTSD in women.

neuroscience↗

bioRxiv2020

Prelimbic-dependent activation of amygdala somatostatin interneurons signals non-aversive cues to promote discrimination.

The amygdala and prelimbic cortex (PL) communicate during fear discrimination retrieval, but how they coordinate to discriminate a non-threatening stimulus is unknown. Here, we show that somatostatin interneurons (SOM) in the basolateral amygdala (BLA) become active specifically during learned non-threatening cues, when they block sensory-evoked phase resetting of theta-oscillations. Further, we show that SOM activation is PL-dependent, and promotes discrimination of non-threat. Thus, fear discrimination engages PL-dependent coordination of BLA SOM responses to non-threatening stimuli.

neuroscience↗

bioRxiv2020

Salient Safety Conditioning Improves Novel Discrimination Learning

Generalized fear is one purported mechanism of anxiety that is a target of clinical and basic research. Impaired fear discrimination has been primarily examined from the perspective of increased fear learning, rather than how learning about non-threatening stimuli affects fear discrimination. To address this question, we tested how three Safety Conditioning protocols with varied levels of salience allocated to the safety cue compared to classic Fear Conditioning in their impact on subsequent innate anxiety, and differential fear learning of new aversive and neutral cues. Using a high anxiety strain of mice (129SvEv, Taconic), we show that Fear Conditioned animals show little exploration of the anxiogenic center of an open field 24 hours later, and poor discrimination during new differential conditioning 7 days later. Three groups of mice underwent Safety Conditioning, (i) the safety tone was unpaired with a shock, (ii) the safety tone was unpaired with the shock and co-terminated with a house light signaling the end of the safety period, and (iii) the safety tone was unpaired with the shock and its beginning co-occurred with a house light, signaling the start of a safety period. Mice from all Safety Conditioning groups showed higher levels of open field exploration than the Fear Conditioned mice 24 hours after training. Furthermore, Safety Conditioned animals showed improved discrimination learning of a novel non-threat, with the Salient Beginning safety conditioned group performing best. These findings indicate that high anxiety animals benefit from salient safety training to improve exploration and discrimination of new non-threating stimuli. Highlights O_LISafety training using salient cues improves safety learning in high anxiety mice C_LIO_LISalient Safety training improves novel fear discrimination learning C_LIO_LISafety training improves exploration in a novel anxiogenic environment C_LI

neuroscience↗