Sexually Dimorphic Control of Parenting Behavior by the Medial Amygdala.

Social behaviors, including behaviors directed toward young offspring, exhibit striking sex differences. Understanding how these sexually dimorphic behaviors are regulated at the level of circuits and transcriptomes will provide insights into neural mechanisms of sex-specific behaviors. Here, we uncover a sexually dimorphic role of the medial amygdala (MeA) in governing parental and infanticidal behaviors. Contrary to traditional views, activation of GABAergic neurons in the MeA promotes parental behavior in females, while activation of this population in males differentially promotes parental versus infanticidal behavior in an activity-level-dependent manner. Through single-cell transcriptomic analysis, we found that molecular sex differences in the MeA are specifically represented in GABAergic neurons. Collectively, these results establish crucial roles for the MeA as a key node in the neural circuitry underlying pup-directed behaviors and provide important insight into the connection between sex differences across transcriptomes, cells, and circuits in regulating sexually dimorphic behavior.

Tobacco-Specific Nitrosamines in the Tobacco and Mainstream Smoke of Commercial Little Cigars.

Cigars are among the broad variety of tobacco products that have not been as extensively studied and characterized as cigarettes. Small cigars wrapped in a tobacco-containing sheet, commonly referred to as little cigars, are a subcategory that are similar to conventional cigarettes with respect to dimensions, filters, and overall appearance. Tobacco-specific nitrosamines (TSNAs) are carcinogens in the tobacco used in both little cigars and cigarettes. This study uses a validated high-performance liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) method to measure the TSNAs 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) in the tobacco filler and the nonintense International Organization for Standardization smoking regimen, ISO 3308, and the newer ISO 20778 Cigarette Intensive (CI) smoking regimen mainstream smoke of 60 commercial little cigars. Tobacco filler NNK and NNN quantities ranged from 26 to 2950 and 1440 to 12 100 ng/g tobacco, respectively. NNK and NNN by the ISO nonintense smoking regimen ranged from 89 to 879 and 200 to 1540 ng/cigar, respectively; by the CI regimen, NNK and NNN ranged from 138 to 1570 and 445 to 2780 ng/cigar, respectively. The average transfer (%) for NNK and NNN from tobacco filler to mainstream smoke was 24% and 36% by the ISO nonintense and CI smoking regimens, respectively. By the ISO nonintense and CI smoking regimens, mainstream smoke NNK and NNN yields showed a moderate to strong correlation (ISO nonintense, R2 = 0.60-0.68, p < 0.0001; CI, R2 = 0.78-0.81, p < 0.0001) with tobacco filler NNK and NNN quantities. In addition, the mainstream smoke NNK and NNN yields of little cigars were determined to be 3- to 5-fold higher compared to previously tested commercial cigarettes. The mainstream smoke NNK and NNN yields have wide variation among commercial little cigars and suggest that, despite design similarities to cigarettes, machine-smoke yields of carcinogenic TSNAs are higher in little cigars.

Competition for mates and the improvement of nonsexual fitness.

Competition for mates can be a major source of selection, not just on secondary sexual traits but across the genome. Mate competition strengthens selection on males via sexual selection, which typically favors healthy, vigorous individuals and, thus, all genetic variants that increase overall quality. However, recent studies suggest another major effect of mate competition that could influence genome-wide selection: Sexual harassment by males can drastically weaken selection on quality in females. Because of these conflicting effects, the net effect of mate competition is uncertain, although perhaps not entirely unpredictable. We propose that the environment in which mate competition occurs mediates the importance of sexual selection relative to sexual conflict and, hence, the net effect of mate competition on nonsexual fitness. To test this, we performed experimental evolution with 63 fruit fly populations adapting to novel larval conditions where each population was maintained with or without mate competition. In half the populations with mate competition, adults interacted in simple, high-density environments. In the remainder, adults interacted in more spatially complex environments in which male-induced harm is reduced. Populations evolving with mate competition in the complex environment adapted faster to novel larval environments than did populations evolving without mate competition or with mate competition in the simple environment. Moreover, mate competition in the complex environment caused a substantial reduction in inbreeding depression for egg-to-adult viability relative to the other two mating treatments. These results demonstrate that the mating environment has a substantial and predictable effect on nonsexual fitness through adaptation and purging.

Cerebral Hyperperfusion and Delayed Coma Recovery after Subdural Hematoma Evacuation.

Acute subdural hematoma is a devastating neurological injury with significant morbidity and mortality. In patients with large subdural hematoma resulting in compression of the underlying brain and lateral brain shift, severe neurological deficits and coma can occur. Emergent neurosurgical decompression is a life-saving intervention which improves mortality and neurological function. Persistent coma despite subdural hematoma evacuation is often the result of persistent midline shift, cerebral infarctions related to initial elevated intracranial pressure and herniation, nonconvulsive seizures, and other metabolic and infectious causes; however, a subset of patients remains comatose without a discernable etiology. In this report, we describe an elderly patient who remained comatose without a known cause for several weeks after subdural hematoma evacuation and was found to have delayed cerebral hyperperfusion on brain imaging. After several days, there was marked recovery of consciousness which occurred in a timeframe that matched improvement in brain imaging findings. Cerebral hyperperfusion following subdural hematoma evacuation requires further investigation, and should be considered as a cause of persistent but potentially recoverable coma.

Case 279: Central-Variant Posterior Reversible Encephalopathy Syndrome.

HistoryA 25-year-old woman with recently diagnosed systemic lupus erythematosus and class IV lupus nephritis confirmed with biopsy and treated with mycophenolate mofetil presented with a 2-day history of progressively worsening edema of her face and lower extremities. She had no antecedent infection or vaccination. She was admitted to the hospital and treated with methylprednisolone, furosemide, and C1 esterase inhibitor. On hospital day 2, she experienced a witnessed generalized tonic-clonic seizure. At that time, she became hypoxic and was intubated for airway protection. Her laboratory study results preceding the seizure were remarkable for hyponatremia, with a blood sodium level of 122 mEq/L (122 mmol/L) (normal range, 135-145 mEq/L [134-145 mmol/L]), which was corrected to 137 mEq/L (137 mmol/L) over 48 hours. Same-day cerebrospinal fluid analysis was unremarkable, and unenhanced head CT findings (not shown) were normal, with no evidence of intracranial hemorrhage or edema.Her subsequent hospital course was complicated by renal failure requiring continuous renal replacement therapy, hypertension (systolic blood pressure ranging from 140 to 190 mm Hg), anemia requiring blood transfusions, thrombocytopenia, and pneumonia. She remained intubated with a limited neurologic examination due to sedative medications until hospital day 10. After extubation, she was noted to have a right gaze preference. She was able to speak in short phrases and follow simple commands. Neurologic examination was notable for drowsiness, right gaze deviation, direction-changing torsional nystagmus, horizontal ophthalmoplegia, and generalized symmetric weakness without upper motor neuron signs. The following day (hospital day 11), unenhanced MRI of the brain was performed along with MR angiography of the brain. Biopsy of the temporal artery was normal, without evidence of inflammation.

Case 279.

HistoryA 25-year-old woman with recently diagnosed systemic lupus erythematosus and class IV lupus nephritis confirmed with biopsy and treated with mycophenolate mofetil presented with a 2-day history of progressively worsening edema of her face and lower extremities. She had no antecedent infection or vaccination. She was admitted to the hospital and treated with methylprednisolone, furosemide, and C1 esterase inhibitor. On hospital day 2, she experienced a witnessed generalized tonic-clonic seizure. At that time, she became hypoxic and was intubated for airway protection. Her laboratory study results preceding the seizure were remarkable for hyponatremia, with a blood sodium level of 122 mEq/L (122 mmol/L) (normal range, 135-145 mEq/L [134-145 mmol/L]), which was corrected to 137 mEq/L (137 mmol/L) over 48 hours. Same-day cerebrospinal fluid analysis was unremarkable, and unenhanced head CT findings (not shown) were normal, with no evidence of intracranial hemorrhage or edema.

The evolution and fate of diversity under hard and soft selection.

How genetic variation arises and persists over evolutionary time despite the depleting effects of natural selection remains a long-standing question. Here, we investigate the impacts of two extreme forms of population regulation-at the level of the total, mixed population (hard selection) and at the level of local, spatially distinct patches (soft selection)-on the emergence and fate of diversity under strong divergent selection. We find that while the form of population regulation has little effect on rates of diversification, it can modulate the long-term fate of genetic variation, diversity being more readily maintained under soft selection compared to hard selection. The mechanism responsible for coexistence is negative frequency-dependent selection which, while present initially under both forms of population regulation, persists over the long-term only under soft selection. Importantly, coexistence is robust to continued evolution of niche specialist types under soft selection but not hard selection. These results suggest that soft selection could be a general mechanism for the maintenance of ecological diversity over evolutionary time scales.

Encephalopathy only stroke codes (EoSC) do not result in rt-PA treatments.

BACKGROUND: Isolated mental status changes as a presenting sign (EoSC+), are not uncommon stroke code triggers. As stroke alerts, they still require the same intensive resources be applied. We previously showed that EoSC+ strokes (EoSC+ Stroke+) account for 0.1-0.2% of all codes. Whether these result in thrombolytic treatment (rt-PA), and the characteristics/ risk factor profiles of EoSC+ Stroke+ patients, have not been reported. METHODS: Retrospective analysis of stroke codes from an IRB approved registry, from 2004 to 2018, was performed. EoSC+ was defined as a NIHSS>0 for Q1a, 1b, or 1c with remaining elements scored 0. Characteristics and risk factors were compared for EoSC+, EoSC-, EoSC+ Stroke+, and rt-PA (EoSC+ Stroke+TPA+) patients. RESULTS: EoSC+ occurred in 55/2982 (1.84%) of all stroke codes. EoSC+ Stroke+ occurred in 8/55 (14.5%) of EoSC+ codes and 8/2982 (0.27%) of all stroke codes. 6/8 (75%) of EoSC+ Stroke+ scored NIHSS=1. When comparing EoSC++versus EoSC-, Hispanic ethnicity (p=0.009), hypertension (p=0.02), and history of stroke/TIA (p=0.002) were less common in EoSC+. No demographic/risk factor differences were noted for EoSC+ Stroke+ vs. EoSC+ Stroke-. No cases of rt-PA eligibility/treatment were noted. In EoSC+ Stroke+ analysis, imaging positive stroke/intracranial hemorrhage was noted on only 3 cases (3/2982=0.10% of all stroke codes) and none were posterior stroke. CONCLUSIONS: EoSC+ rarely results in stroke/TIA (0.27%) or stroke (0.10%), and in our analysis never (0%) resulted in rt-PA. Sub-analysis did not show missed rt-PA or posterior strokes. Understanding characteristics, and knowing that EoSC+ Stroke+ patients are unlikely to receive rt-PA, may help triage stroke resources.

Moyamoya Presenting after Whole Body Cryotherapy.

BACKGROUND PURPOSE: Moyamoya syndrome is the progressive stenosis of intracranial carotids with secondary collateralization. Whole body cryotherapy (WBC) involves external cooling and is used in holistic and sports medicine, its neurologic effects are unknown. CASE REPORT: We report a first case of symptoms of moyamoya syndrome presenting following WBC and diagnosed with classic MRI ( "Brush Sign", "Ivy sign") and digital subtracted angiography. CONCLUSION: WBC may provoke symptoms of moyamoya syndrome possibly through hyperventilation or vasoconstriction. Practitioners should be aware of possible consequences of WBC in patients with poor cerebrovascular reserve.

Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2-/- mice.

Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3), severe liver diseases associated with genetic defects in the biliary bile acid transporter bile salt export pump (BSEP; ABCB11) or phosphatidylcholine transporter multidrug resistance protein 3 (MDR3; ABCB4), respectively. Mdr2-/- mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the nonmicelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep-/- mice could protect Mdr2-/- mice from progressive liver damage. We generated double-KO (DKO: Bsep-/- and Mdr2-/- ) mice. Their bile acid composition resembles that of Bsep-/- mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBAs), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2-/- littermates. The livers of DKO mice have gene expression profiles very similar to Bsep-/- mice, with 4,410 of 6,134 gene expression changes associated with the Mdr2-/- mutation being suppressed. Feeding with THBAs partially alleviates liver damage in the Mdr2-/- mice. Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2-/- (PFIC3) mutation.

Differential Regulation of NMDA Receptor-Mediated Transmission by SK Channels Underlies Dorsal-Ventral Differences in Dynamics of Schaffer Collateral Synaptic Function.

Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, we investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses in the mouse hippocampus. We find that, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to θ frequency patterns of stimulation. In contrast to dorsal hippocampus, θ frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. Our results indicate that all these differences in postsynaptic function are due to an enhanced activation of SK-type K+ channels that suppresses NMDAR-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, our findings indicate that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing, and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors.SIGNIFICANCE STATEMENT Differences in short- and long-term plasticity at Schaffer collateral (SC) synapses in the dorsal and ventral hippocampus likely contribute importantly to the distinct roles of these regions in cognition and behavior. Although dorsal and ventral CA1 pyramidal cells exhibit markedly different gene expression profiles, how these differences influence plasticity at SC synapses is unclear. Here we report that increased mRNA levels for the SK3 subunit of SK-type K+ channels in ventral pyramidal cells is associated with an enhanced activation of SK channels that strongly suppresses NMDAR activation at ventral SC synapses. This leads to striking differences in multiple aspects of synaptic transmission at dorsal and ventral SC synapses and underlies the reduced ability of ventral SC synapses to undergo LTP.

The physical environment mediates male harm and its effect on selection in females.

Recent experiments indicate that male preferential harassment of high-quality females reduces the variance in female fitness, thereby weakening natural selection through females and hampering adaptation and purging. We propose that this phenomenon, which results from a combination of male choice and male-induced harm, should be mediated by the physical environment in which intersexual interactions occur. Using Drosophila melanogaster, we examined intersexual interactions in small and simple (standard fly vials) versus slightly more realistic (small cages with spatial structure) environments. We show that in these more realistic environments, sexual interactions are less frequent, are no longer biased towards high-quality females, and that overall male harm is reduced. Next, we examine the selective advantage of high- over low-quality females while manipulating the opportunity for male choice. Male choice weakens the viability advantage of high-quality females in the simple environment, consistent with previous work, but strengthens selection on females in the more realistic environment. Laboratory studies in simple environments have strongly shaped our understanding of sexual conflict but may provide biased insight. Our results suggest that the physical environment plays a key role in the evolutionary consequences of sexual interactions and ultimately the alignment of natural and sexual selection.

Response Rates to Anticonvulsant Trials in Patients with Triphasic-Wave EEG Patterns of Uncertain Significance.

BACKGROUND: Generalized triphasic waves (TPWs) occur in both metabolic encephalopathies and non-convulsive status epilepticus (NCSE). Empiric trials of benzodiazepines (BZDs) or non-sedating AED (NSAEDs) are commonly used to differentiate the two, but the utility of such trials is debated. The goal of this study was to assess response rates of such trials and investigate whether metabolic profile differences affect the likelihood of a response. METHODS: Three institutions within the Critical Care EEG Monitoring Research Consortium retrospectively identified patients with unexplained encephalopathy and TPWs who had undergone a trial of BZD and/or NSAEDs to differentiate between ictal and non-ictal patterns. We assessed responder rates and compared metabolic profiles of responders and non-responders. Response was defined as resolution of the EEG pattern and either unequivocal improvement in encephalopathy or appearance of previously absent normal EEG patterns, and further categorized as immediate (within <2 h of trial initiation) or delayed (>2 h from trial initiation). RESULTS: We identified 64 patients with TPWs who had an empiric trial of BZD and/or NSAED. Most patients (71.9%) were admitted with metabolic derangements and/or infection. Positive clinical responses occurred in 10/53 (18.9%) treated with BZDs. Responses to NSAEDs occurred in 19/45 (42.2%), being immediate in 6.7%, delayed but definite in 20.0%, and delayed but equivocal in 15.6%. Overall, 22/64 (34.4%) showed a definite response to either BZDs or NSAEDs, and 7/64 (10.9%) showed a possible response. Metabolic differences of responders versus non-responders were statistically insignificant, except that the 48-h low value of albumin in the BZD responder group was lower than in the non-responder group. CONCLUSIONS: Similar metabolic profiles in patients with encephalopathy and TPWs between responders and non-responders to anticonvulsants suggest that predicting responders a priori is difficult. The high responder rate suggests that empiric trials of anticonvulsants indeed provide useful clinical information. The more than twofold higher response rate to NSAEDs suggests that this strategy may be preferable to BZDs. Further prospective investigation is warranted.

Friedman's Gradient-Boosting Algorithm Predicts Lactate-Pyruvate Ratio Trends in Cases of Intracerebral Hemorrhages.

OBJECTIVE: The local effects of an intracerebral hemorrhage (ICH) on surrounding brain tissue can be detected bedside using multimodal brain monitoring techniques. The aim of this study is to design a gradient boosting regression model using the R package boostmtree with the ability to predict lactate-pyruvate ratio measurements in ICH. METHODS: We performed a retrospective analysis of 6 spontaneous ICH and 6 traumatic ICH patients who underwent surgical removal of the clot with microdialysis catheters placed in the perihematomal zone. Predictors of glucose, lactate, pyruvate, age, sex, diagnosis, and operation status were used to design our model. RESULTS: In a holdout analysis, the model forecasted lactate-pyruvate ratio trends in a representative in-sample testing set. We anticipate that boostmtree could be applied to designs of similar regression models to analyze trends in other multimodal monitoring features across other types of acute brain injury. CONCLUSIONS: The model successfully predicted hourly lactate-pyruvate ratios in spontaneous ICH and traumatic ICH cases after the hemorrhage evacuation and displayed significantly better performance than linear models. Our results suggest that boostmtree may be a powerful tool in developing more advanced mathematical models to assess other multimodal monitoring parameters for cases in which the perihematomal environment is monitored.

iPad-Based Neurocognitive Testing (ImPACT-QT) in Acute Adult Mild Traumatic Brain Injury/Concussion: Study on Practicality and Bedside Cognitive Scores in a Level-1 Trauma Center.

BACKGROUND: There lacks rapid standardized bedside testing to screen cognitive deficits following mild traumatic brain injury (mTBI). Immediate Post-Concussion Assessment & Cognitive Testing-Quick Test (ImPACT-QT) is an abbreviated-iPad form of computerized cognitive testing. The aim of this study is to test ImPACT-QT utility in inpatient settings. We hypothesize ImPACT-QT is feasible in the acute trauma setting. METHOD: Trauma patients ages 12-70 were administered ImPACT-QT (09/2022-09/2023). Encephalopathic/medically unstable patients were excluded. Mild traumatic brain injury was defined as documented-head trauma with loss-of-consciousness <30 minutes and arrival Glasgow Coma Scale 13-15. Patients answered Likert-scale surveys. Bivariate analyses compared demographics, attention, motor speed, and memory scores between mTBI and non-TBI controls. Multivariable logistic regression assessed memory score as a predictor of mTBI diagnosis. RESULTS: Of 233 patients evaluated (36 years [IQR 23-50], 71% [166/233] female), 179 (76%) were mTBI patients. For all patients, mean test-time was 9.3 ± 2 minutes with 93% (73/76) finding the test "easy to understand." Mild traumatic brain injury patients than non-TBI control had lower memory scores (25 [IQR 7-100] vs 43 [26-100], P = .001) while attention (5 [1-23] vs 11 [1-32]) and motor score (14 [3-28] vs 13 [4-32]) showed no significant differences. Multivariable-regression (adjustment: age, sex, race, education level, ISS, and time to test) demonstrated memory score predicted mTBI positive status (OR .96, CI .94-.98, P = .004). DISCUSSION: Immediate Post-Concussion Assessment & Cognitive Testing-Quick Test is feasible in trauma patients. Preliminary findings suggest acute mTBIs have lower memory but not attention/motor scores vs non-TBI trauma controls.

Complementation testing identifies causal genes at quantitative trait loci underlying fear related behavior.

Knowing the genes involved in quantitative traits provides a critical entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. Here we address a key step towards that goal by deploying a test that directly queries whether a gene mediates the effect of a quantitative trait locus (QTL). To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six QTLs, and identified six genes. Four genes, Lsamp, Ptprd, Nptx2 and Sh3gl, have known roles in synapse function; the fifth gene, Psip1, is a transcriptional co-activator not previously implicated in behavior; the sixth is a long non-coding RNA 4933413L06Rik with no known function. Single nucleus transcriptomic and epigenetic analyses implicated excitatory neurons as likely mediating the genetic effects. Surprisingly, variation in transcriptome and epigenetic modalities between inbred strains occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results open a bottleneck in using genetic mapping of QTLs to find novel biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.