"I'm more than my sport": Exploring the dynamic processes of identity change in athletic retirement.

Retirement is one of the most impactful career transitions athletes face. Researchers recognise the role that athletic identity plays in this, but analysis of identity content and change processes is limited. Addressing this gap, we conducted a qualitative study exploring the experience of identity change in 21 competitive and successful elite athletes who had retired from sport. All participated in a one-session psychoeducational program that explored the challenges of transitioning out of sport before being interviewed about their understanding of identity in sport, and their experiences negotiating identity loss and change in retirement. Using reflexive thematic analysis, we identified three themes: (i) the role of identity and self-categorizations in shaping sport performance, (ii) adjusting to identity loss (with subthemes indicating that this experience varied depending on the extent to which a person had multiple or exclusive identities), and (iii) attempts to remoor identity in the transition (with subthemes of searching for a new identity and actively repurposing identity). We interpret these themes through the lens of the Social Identity Model of Identity Change and show that this provides a framework for extending our understanding the complexities of identity change associated with retirement from elite sport.

Insular cortex subregions have distinct roles in cued heroin seeking after extinction learning and prolonged withdrawal in rats.

Evidence indicates that the anterior (aIC), but not posterior (pIC), insular cortex promotes cued reinstatement of cocaine seeking after extinction in rats. It is unknown whether these subregions also regulate heroin seeking and whether such involvement depends on prior extinction learning. To address these questions, we used baclofen and muscimol (BM) to inactivate the aIC or pIC bilaterally during a seeking test after extinction or prolonged withdrawal from heroin. Male Sprague-Dawley rats in the extinction groups underwent 10+ days of heroin self-administration, followed by 6+ days of extinction sessions, and subsequent cued or heroin-primed reinstatement. Results indicate that aIC inactivation increased cued reinstatement of heroin seeking after extinction, whereas pIC inactivation prevented cued reinstatement. To determine whether these effects were extinction-dependent, we conducted a subsequent study using both sexes with prolonged withdrawal. Male and female rats in the withdrawal groups underwent 10+ days of heroin self-administration, followed by cued seeking tests after 1 and 14 days of homecage withdrawal to measure incubation of heroin craving. In this case, the findings indicate that aIC inactivation had no effect on incubation of heroin craving after withdrawal in either sex, whereas pIC inactivation decreased heroin craving only in males. These findings suggest that the aIC and pIC have opposing roles in suppressing vs promoting cued heroin seeking after extinction and that these roles are distinct from those in cocaine seeking. Moreover, the incubation of craving results suggest that new contingency learning is necessary to recruit the aIC in cued heroin seeking.

Intranasal parainfluenza virus type 5 (PIV5)-vectored RSV vaccine is safe and immunogenic in healthy adults in a phase 1 clinical study.

Respiratory syncytial virus (RSV) can lead to serious disease in infants, and no approved RSV vaccine is available for infants. This first in-human clinical trial evaluated a single dose of BLB201, a PIV5-vectored RSV vaccine administrated via intranasal route, for safety and immunogenicity in RSV-seropositive healthy adults (33 to 75 years old). No severe adverse events (SAEs) were reported. Solicited local and systemic AEs were reported by <50% of participants and were mostly mild in intensity. Vaccine virus shedding was detected in 17% of participants. Nasal RSV-specific immunoglobulin A responses were detected in 48%, the highest level observed in adults among all intranasal RSV vaccines evaluated in humans. RSV-neutralizing antibodies titers in serum rose ≥1.5-fold. Peripheral blood RSV F-specific CD4+ and CD8+ T cells increased from ≤0.06% at baseline to ≥0.26 and 0.4% after vaccination, respectively, in >93% participants. The safety and immunogenicity profile of BLB201 in RSV-seropositive adults supports the further clinical development of BLB201.

Still a "hidden island"? The rodent insular cortex in drug seeking, reward, and risk.

The insular cortex (IC) is implicated in risky decision making and drug-seeking behaviors, in a manner dissociable from natural reward seeking. However, evidence from rodent studies of motivated behaviors suggests that the role of the IC is not always consistent across procedures. Moreover, there is evidence of dissociation of function between posterior (pIC) and anterior (aIC) subregions in these behaviors. Under which circumstances, and by which mechanisms, these IC subregions are recruited to regulate motivated behaviors remains unclear. Here, we discuss evidence of rodent pIC and aIC function across drug-related behaviors, natural reward seeking, and decision making under risk and highlight procedural differences that may account for seemingly conflicting findings. Although gaps in the literature persist, we hypothesize that IC activity is broadly important for selection of appropriate behaviors based on learned action-outcome contingencies and that associated risk is sufficient, but not necessary, to recruit the aIC in reward seeking without involving the pIC.

Infralimbic Projections to the Nucleus Accumbens Shell and Amygdala Regulate the Encoding of Cocaine Extinction Learning.

Prior evidence indicates that the infralimbic cortex (IL) mediates the ongoing inhibition of cocaine seeking following self-administration and extinction training in rats, specifically through projections to the nucleus accumbens shell (NAshell). Our own data indicate that IL activity immediately following an unreinforced lever press is critical for encoding the extinction contingencies in such procedures. Whether extinction encoding requires activity in the IL exclusively or also activity in its outputs, such as those to the NAshell and amygdala, is unknown. To address this issue, we used a closed-loop optogenetic approach in female and male Sprague Dawley rats to silence IL-NAshell or IL-amygdala activity following an unreinforced lever press during extinction training. Optical illumination (20 s) was given either immediately after a lever press or following a 20 s delay. IL-NAshell inhibition immediately following an unreinforced lever press increased lever pressing during extinction training and impaired retention of extinction learning, as assessed during subsequent extinction sessions without optical inhibition. Likewise, IL-amygdala inhibition given in the same manner impaired extinction retention during sessions without inhibition. Control experiments indicate that critical encoding of extinction learning does not require activity in these pathways beyond the initial 20 s post-lever press period, as delayed IL-NAshell and IL-amygdala inhibition had no effect on extinction learning. These results suggest that a larger network extending from the IL to the NAshell and amygdala is involved in encoding extinction contingencies following cocaine self-administration.SIGNIFICANCE STATEMENT Infralimbic cortex (IL) activity following an unreinforced lever press during extinction learning encodes the extinction of cocaine-seeking behavior. However, the larger circuitry controlling such encoding has not been investigated. Using closed-loop optogenetic pathway targeting, we found that inhibition of IL projections to the nucleus accumbens shell and to the amygdala impaired the extinction of cocaine seeking. Importantly, these effects were only observed when activity was disrupted during the first 20 s post-lever press and not when given following a 20 s delay. These findings suggest that successful cocaine extinction encoding requires activity across a larger circuit beyond simply inputs to the IL.

Female Genital Fibroblasts Diminish the In Vitro Efficacy of PrEP against HIV.

The efficacy of HIV pre-exposure prophylaxis (PrEP) is high in men who have sex with men, but much more variable in women, in a manner largely attributed to low adherence. This reduced efficacy, however, could also reflect biological factors. Transmission to women is typically via the female reproductive tract (FRT), and vaginal dysbiosis, genital inflammation, and other factors specific to the FRT mucosa can all increase transmission risk. We have demonstrated that mucosal fibroblasts from the lower and upper FRT can markedly enhance HIV infection of CD4+ T cells. Given the current testing of tenofovir disoproxil fumarate, cabotegravir, and dapivirine regimens as candidate PrEP agents for women, we set out to determine using in vitro assays whether endometrial stromal fibroblasts (eSF) isolated from the FRT can affect the anti-HIV activity of these PrEP drugs. We found that PrEP drugs exhibit significantly reduced antiviral efficacy in the presence of eSFs, not because of decreased PrEP drug availability, but rather of eSF-mediated enhancement of HIV infection. These findings suggest that drug combinations that target both the virus and infection-promoting factors in the FRT-such as mucosal fibroblasts-may be more effective than PrEP alone at preventing sexual transmission of HIV to women.

Single-cell glycomics analysis by CyTOF-Lec reveals glycan features defining cells differentially susceptible to HIV.

High-parameter single-cell phenotyping has enabled in-depth classification and interrogation of immune cells, but to date has not allowed for glycan characterization. Here, we develop CyTOF-Lec as an approach to simultaneously characterize many protein and glycan features of human immune cells at the single-cell level. We implemented CyTOF-Lec to compare glycan features between different immune subsets from blood and multiple tissue compartments, and to characterize HIV-infected cell cultures. Using bioinformatics approaches to distinguish preferential infection of cellular subsets from viral-induced remodeling, we demonstrate that HIV upregulates the levels of cell-surface fucose and sialic acid in a cell-intrinsic manner, and that memory CD4+ T cells co-expressing high levels of fucose and sialic acid are highly susceptible to HIV infection. Sialic acid levels were found to distinguish memory CD4+ T cell subsets expressing different amounts of viral entry receptors, pro-survival factors, homing receptors, and activation markers, and to play a direct role in memory CD4+ T cells' susceptibility to HIV infection. The ability of sialic acid to distinguish memory CD4+ T cells with different susceptibilities to HIV infection was experimentally validated through sorting experiments. Together, these results suggest that HIV remodels not only cellular proteins but also glycans, and that glycan expression can differentiate memory CD4+ T cells with vastly different susceptibility to HIV infection.

Living cells have a sugar coating. These sugars include molecules called glycans, which help cells interact with the outside world. The types of sugars on cells can affect their properties, including potentially their susceptibility to infection by viruses, such as the human immunodeficiency virus, HIV. To date, most research examining cells susceptible to HIV has focused on cell surface proteins, not sugars. To study these proteins, researchers had previously covered them in metal-studded antibodies (which stick to proteins) and used a technique called cytometry time of flight, or CyTOF for short, to quantify the levels of these proteins on the surface of cells susceptible to HIV. Adapting this tool to investigate sugars could answer questions about HIV infection. For example, does the virus prefer to infect cells coated in certain sugar molecules? And does it change the pattern of sugars on the surface of the cells it infects? Ma et al. adapted CyTOF to use molecules called lectins (which stick to sugars) in conjunction with the metal-studded antibodies. This made it possible to simultaneously measure the levels of 34 different proteins and 5 different types of sugars on individual cells. The pattern of sugars on the surface of cells from the immune system differed depending on what tissues the cells came from, and what types of cells they were. The results showed that HIV preferred to infect memory CD4 T cells with high levels of two types of sugar: fucose and sialic acid. Furthermore, during infection, the levels of both these sugars increased. Current treatments for HIV keep virus levels low but do not cure the infection. Further research could determine whether sugars have a role to play in HIV persistence. It is possible that the sugar patterns preferred by the virus help it to avoid detection. A clearer understanding of cell surface sugars could lead to sugar-targeting drugs that kill infected cells.

mRNA vaccine-induced T cells respond identically to SARS-CoV-2 variants of concern but differ in longevity and homing properties depending on prior infection status.

While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.

Vaccination is one of the best ways to prevent severe COVID-19. Two doses of mRNA vaccine protect against serious illness caused by the coronavirus SARS-CoV-2. They do this, in part, by encouraging the immune system to make specialised proteins known as antibodies that recognise the virus. Most of the vaccine research so far has focussed on these antibodies, but they are only one part of the immune response. Vaccines also activate immune cells called T cells. These cells have two main roles, coordinating the immune response and killing cells infected with viruses. It is likely that they play a key role in preventing severe COVID-19. There are many kinds of T cells, each with a different role. Currently, the identity and characteristics of the T cells that protect against COVID-19 is unclear. Different types of T cells have unique proteins on their surface. Examining these proteins can reveal details about how the T cells work, which part of the virus they recognise, and which part of the body they protect. A tool called cytometry by time of flight allows researchers to measure these proteins, one cell at a time. Using this technique, Neidleman, Luo et al. investigated T cells from 11 people before vaccination and after their first and second doses. Five people had never had COVID-19 before, and six had already recovered from COVID-19. Neidleman, Luo et al. found that the T cells recognizing SARS-CoV-2 in the two groups differed. In people who had never had COVID-19 before, the second dose of vaccine improved the quality and quantity of the T cells. The same was not true for people who had already recovered from COVID-19. However, although their T cells did not improve further after a second vaccine dose, they did show signs that they might offer more protection overall. The proteins on the cells suggest that they might last longer, and that they might specifically protect the nose, throat and lungs. Neidleman, Luo et al. also found that, for both groups, T cells activated by vaccination responded in the same way to different variants of the virus. This work highlights the importance of getting both vaccine doses for people who have never had COVID-19. It also suggests that vaccination in people who have had COVID-19 may generate better T cells. Larger studies could show whether these patterns remain true across the wider population. If so, it is possible that delivering vaccines to the nose or throat could boost immunity by mimicking natural infection. This might encourage T cells to make the surface proteins that allow them to home to these areas.

Protracted yet Coordinated Differentiation of Long-Lived SARS-CoV-2-Specific CD8+ T Cells during Convalescence.

CD8+ T cells can potentiate long-lived immunity against COVID-19. We screened longitudinally-sampled convalescent human donors against SARS-CoV-2 tetramers and identified a participant with an immunodominant response against residues 322 to 311 of nucleocapsid (Nuc322-331), a peptide conserved in all variants of concern reported to date. We conducted 38-parameter cytometry by time of flight on tetramer-identified Nuc322-331-specific CD8+ T cells and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins, and took 32 serological measurements. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and Ab pillars of adaptive immunity. Over the approximately six month period of convalescence monitored, we observed a slow and progressive decrease in the activation state and polyfunctionality of Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph node-homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence into a state characteristic of long-lived, self-renewing memory.

Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19.

Although T cells are likely players in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity, little is known about the phenotypic features of SARS-CoV-2-specific T cells associated with recovery from severe coronavirus disease 2019 (COVID-19). We analyze T cells from 34 individuals with COVID-19 with severity ranging from mild (outpatient) to critical, culminating in death. Relative to individuals who succumbed, individuals who recovered from severe COVID-19 harbor elevated and increasing numbers of SARS-CoV-2-specific T cells capable of homeostatic proliferation. In contrast, fatal COVID-19 cases display elevated numbers of SARS-CoV-2-specific regulatory T cells and a time-dependent escalation in activated bystander CXCR4+ T cells, as assessed by longitudinal sampling. Together with the demonstration of increased proportions of inflammatory CXCR4+ T cells in the lungs of individuals with severe COVID-19, these results support a model where lung-homing T cells activated through bystander effects contribute to immunopathology, whereas a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.

Productive Infection of Human Breast Cancer Cell Lines with Human Cytomegalovirus (HCMV).

Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.

Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence.

CD8+ T cells are important antiviral effectors that can potentiate long-lived immunity against COVID-19, but a detailed characterization of these cells has been hampered by technical challenges. We screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19 against a collection of SARS-CoV-2 tetramers, and identified one participant with an immunodominant response against Nuc322-331, a peptide that is conserved in all the SARS-CoV-2 variants-of-concern reported to date. We conducted 38-parameter CyTOF phenotyping on tetramer-identified Nuc322-331-specific CD8+ T cells, and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins from SARS-CoV-2, and took 32 serological measurements on longitudinal specimens from this participant. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and antibody pillars of adaptive immunity. Nuc322-331-specific CD8+ T cells were predominantly central memory T cells, but continually evolved over a ~6-month period of convalescence. We observed a slow and progressive decrease in the activation state and polyfunctionality of the Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph-node homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.

mRNA vaccine-induced T cells respond identically to SARS-CoV-2 variants of concern but differ in longevity and homing properties depending on prior infection status.

While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.

Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19.

Although T cells are likely players in SARS-CoV-2 immunity, little is known about the phenotypic features of SARS-CoV-2-specific T cells associated with recovery from severe COVID-19. We analyzed T cells from longitudinal specimens of 34 COVID-19 patients with severities ranging from mild (outpatient) to critical culminating in death. Relative to patients that succumbed, individuals that recovered from severe COVID-19 harbored elevated and increasing numbers of SARS-CoV-2-specific T cells capable of homeostatic proliferation. In contrast, fatal COVID-19 displayed elevated numbers of SARS-CoV-2-specific regulatory T cells and a time-dependent escalation in activated bystander CXCR4+ T cells. Together with the demonstration of increased proportions of inflammatory CXCR4+ T cells in the lungs of severe COVID-19 patients, these results support a model whereby lung-homing T cells activated through bystander effects contribute to immunopathology, while a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential.

Convalescing coronavirus disease 2019 (COVID-19) patients mount robust T cell responses against SARS-CoV-2, suggesting an important role of T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells and predominantly Tcm cells with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can proliferate homeostatically, and can persist for over 2 months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection and support an important role of SARS-CoV-2-specific T cells in host control of COVID-19.

Roux-en-Y gastric bypass increases GABA-A receptor levels in regions of the rat brain involved in object recognition memory and perceptual acuity.

Roux-en-Y gastric bypass surgery (RYGB), one of the most common and successful procedures for combatting obesity, is associated with post-surgery substance use disorder (SUD) and other addictive behaviors in a subset of patients. We investigated the effects of RYGB on GABA-A receptor levels in the rat brain to identify potential mechanisms of this behavior. The GABAergic system is affected in addiction and has been implicated in the pathology of obesity. We assigned male Sprague-Dawley rats to four groups: standard, low fat diet with sham surgery (control), ad libitum HFD with sham surgery (Sham), calorie restricted HFD with sham surgery (Sham-FR), or HFD with RYGB surgery. Surgery was performed after 8 weeks on the control or HFD diet. Rats maintained their respective diets for 9 weeks post-surgery, then were sacrificed for GABA-A receptor autoradiography using the [3H] Flunitrazepam ligand. We identified increased GABA-A binding in the perirhinal cortex of ad-libitum HFD fed rats compared to normal diet controls. RYGB surgery increased GABA-A in the ectorhinal cortex compared to normal diet controls, and increased binding in the jaw region of the primary somatosensory cortex compared to food-restricted rats that received sham surgery. Hypothalamus GABA-A was also negatively correlated with body weight in the RYGB group, where GABA signaling may play a role in obesity regulation. These results suggest that HFD and RYGB modulate GABA signaling in regions important for object recognition memory, and that increased GABA-A levels in the jaw's perceptual field cortex arise from the surgery itself, independent of caloric restriction.

SARS-CoV-2-specific T cells exhibit unique features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential.

Convalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can homeostatically proliferate, and can persist for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.

The functional networks of a novel environment: Neural activity mapping in awake unrestrained rats using positron emission tomography.

INTRODUCTION: Novel environment stimulation is thought to have an important role in cognitive development and has been shown to encourage exploratory behavior in rats. However, psychopathology or perceived danger or stress can impede this exploratory drive. The balance between brain circuits controlling the exploratory drive elicited by a novel environment, and the avoidance response to stressors, is not well understood. METHODS: Using positron emission tomography (PET) and the glucose analog [18 F]fluorodeoxyglucose (18F-FDG), we assessed awake brain glucose metabolism (BGluM) in rats while in a novel environment (cage of an unfamiliar male rat) and non-novel environment (the animal's home cage). RESULTS: Exposure to the novel environment increased BGluM in regions associated with vision (visual cortex), motor function and motivated behavior (striatum and motor cortex), and anxiety (stria terminalis), and decreased BGluM in regions associated with auditory processing (auditory cortex, insular cortex, inferior colliculus), locomotor activity (globus pallidus, striatum, motor cortex, ventral thalamic nucleus), spatial navigation (retrosplenial cortex), and working memory (hippocampus, cingulate cortex, prelimbic cortex, orbitofrontal cortex). CONCLUSION: These results suggest that the novel cage is a stressful environment that inhibits activity in brain regions associated with exploratory behavior. Patterns of inhibition in the novel cage also support the proposed rat default mode network, indicating that animals are more cognitively engaged in this environment. Additionally, these data support the unique capability of combining FDG-PET with psychopharmacology experiments to examine novelty seeking and brain activation in the context of decision making, risk taking, and cognitive function more generally, along with response to environmental or stress challenges.

Directly to the Point: Dopamine Persistently Enhances Excitability of Direct Pathway Striatal Neurons.

In this issue of Neuron, Lahiri and Bevan (2020) investigate the effects of dopamine release on striatal projection neurons. Using perforated patch recordings and optogenetics, they show that dopamine release persistently enhances the intrinsic excitability of direct pathway striatal neurons.

Functionally Distinct Connectivity of Developmentally Targeted Striosome Neurons.

One long-standing model of striatal function divides the striatum into compartments called striosome and matrix. While some anatomical evidence suggests that these populations represent distinct striatal pathways with differing inputs and outputs, functional investigation has been limited by the methods for identifying and manipulating these populations. Here, we utilize hs599CreER mice as a new tool for targeting striosome projection neurons and testing their functional connectivity. Extending anatomical work, we demonstrate that striosome neurons receive greater synaptic input from prelimbic cortex, whereas matrix neurons receive greater input from primary motor cortex. We also identify functional differences in how striosome and matrix neurons process excitatory input, providing the first electrophysiological method for delineating striatal output neuron subtypes. Lastly, we provide the first functional demonstration that striosome neurons are the predominant striatal output to substantia nigra pars compacta dopamine neurons. These results identify striosome and matrix as functionally distinct striatal pathways.