Integration of Parallel Opposing Memories Underlies Memory Extinction.

Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory. Light and ultrastructural anatomy are consistent with parallel competing memories being combined within mushroom body output neurons that direct avoidance. Indeed, extinction-evoked plasticity in a pair of these neurons neutralizes the potentiated odor response imposed in the network by aversive learning. Therefore, flies track the accuracy of learned expectations by accumulating and integrating memories of conflicting events.

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank.

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear. We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: 'minimally adjusted' controlling for variables such as age and sex, and 'fully adjusted' including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake. There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively. This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.

Lesion correlates of auditory sentence comprehension deficits in post-stroke aphasia.

Auditory sentence comprehension requires coordination of multiple levels of processing: auditory-phonological perception, lexical-semantic comprehension, syntactic parsing and discourse construction, as well as executive functions such as verbal working memory (WM) and cognitive control. This study examined the lesion correlates of sentence comprehension deficits in post-stroke aphasia, building on prior work on this topic by using a different and clinically-relevant measure of sentence comprehension (the Token Test) and multivariate (SCCAN) and connectome-based lesion-symptom mapping methods. The key findings were that lesions in the posterior superior temporal lobe and inferior frontal gyrus (pars triangularis) were associated with sentence comprehension deficits, which was observed in both mass univariate and multivariate lesion-symptom mapping. Graph theoretic measures of connectome disruption were not statistically significantly associated with sentence comprehension deficits after accounting for overall lesion size.

Early-life inflammatory markers and subsequent psychotic and depressive episodes between 10 to 28 years of age.

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10-28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; ß = 0.066; 95%CI:0.020-0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention.

Input Connectivity Reveals Additional Heterogeneity of Dopaminergic Reinforcement in Drosophila.

Different types of Drosophila dopaminergic neurons (DANs) reinforce memories of unique valence and provide state-dependent motivational control [1]. Prior studies suggest that the compartment architecture of the mushroom body (MB) is the relevant resolution for distinct DAN functions [2, 3]. Here we used a recent electron microscope volume of the fly brain [4] to reconstruct the fine anatomy of individual DANs within three MB compartments. We find the 20 DANs of the γ5 compartment, at least some of which provide reward teaching signals, can be clustered into 5 anatomical subtypes that innervate different regions within γ5. Reconstructing 821 upstream neurons reveals input selectivity, supporting the functional relevance of DAN sub-classification. Only one PAM-γ5 DAN subtype γ5(fb) receives direct recurrent feedback from γ5ß'2a mushroom body output neurons (MBONs) and behavioral experiments distinguish a role for these DANs in memory revaluation from those reinforcing sugar memory. Other DAN subtypes receive major, and potentially reinforcing, inputs from putative gustatory interneurons or lateral horn neurons, which can also relay indirect feedback from MBONs. We similarly reconstructed the single aversively reinforcing PPL1-γ1pedc DAN. The γ1pedc DAN inputs mostly differ from those of γ5 DANs and they cluster onto distinct dendritic branches, presumably separating its established roles in aversive reinforcement and appetitive motivation [5, 6]. Tracing also identified neurons that provide broad input to γ5, ß'2a, and γ1pedc DANs, suggesting that distributed DAN populations can be coordinately regulated. These connectomic and behavioral analyses therefore reveal further complexity of dopaminergic reinforcement circuits between and within MB compartments.