Suppressor of cytokine signaling (SOCS) 2 is a negative regulator of growth hormone (GH) signaling that regulates body growth postnatally and neuronal differentiation during development. SOCS2 binds to the GH receptor and inhibits GH signaling, including attenuation of STAT5 activation. Here we describe a new function and mechanism of action for SOCS2. Overexpression of SOCS2 in central nervous system neurons promoted neurite outgrowth, and in PC12 cells, neurite outgrowth was induced under nondifferentiating conditions, leading to inhibition of the neurite-inhibitory GTPase Rho and activation of the neurite-promoting GTPase Rac1. Addition of the epidermal growth factor receptor (EGFR) inhibitors PP3 or AG490 or the Src kinase inhibitor PP2 blocked the SOCS2-induced neurite outgrowth. The overexpressed SOCS2 bound to the EGFR, which was constitutively phosphorylated at Tyr 845 , the Src binding site. Overexpression of the phosphatase SHP-2 reduced the constitutive EGFR phosphorylation and subsequent neurite outgrowth. SOCS2 expression also resulted in a modest 30% decrease in phosphorylation of STAT5b at Tyr 699 , which is the primary site on STAT5 phosphorylated by GH; however, total tyrosine phosphorylation of STAT5 was decreased by 75-80% under basal and epidermal growth factorstimulated conditions. Our findings suggest that SOCS2 regulates EGFR phosphorylation, leading to regulation of neurite outgrowth through a novel pathway that is distinct from GH.

This study sought to test whether the neurobiology of self-processing differentiated depressed adolescents with high suicidality from those with low suicidality and healthy controls (N=119, MAGE= 14.79, SD=1.64, Min=11.3, Max = 17.8). Participants completed a visual self-recognition task in the scanner during which they identified their own or an unfamiliar adolescent face across three emotional expressions (happy, neutral or sad). A 3 Group (HS, LS, HC) by two within subject factors [2 Self conditions (self, other) and 3 Emotions (happy, neutral, sad)] GLM yielded: 1) a main effect of Self condition with all participants showing higher activity in the right occipital, precuneus and fusiform during the self-versus other-face conditions; 2) a main effect of Group where all depressed youth showed higher dorsolateral prefrontal cortex activity than HC across all conditions, and with HS showing higher cuneus and occipital activity versus both LS and HC; and 3) a Group by Self by Emotion interaction with HS showing lower activity in both mid parietal, limbic and prefrontal areas in the Happy self versus other-face condition relative to the LS group, who in turn had less activity compared to HC youth. Covarying for depression severity replicated all results except the third finding; in this subsequent analysis, a Group by Self interaction showed that although HC had similar midline cortical structure (MCS) activity for all faces, LS showed higher MCS activity for the self vs. other faces while HS showed the opposite pattern. Results suggest that the neurophysiology of emotionally charged self-referential information can distinguish depressed, suicidal youth versus non-suicidal depressed and healthy adolescents. Neurophysiological differences and implications for the prediction of suicidality in youth are discussed. General Scientific Summary: Depressed adolescents with high suicidality show less activity in brain areas that support emotional experiences and self-awareness when identifying their own face, suggesting that abnormal self-processing may be associated with greater suicide risk.

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BACKGROUND The ventral striatum (VS) and striatal network supports goal motivated behavior. Identifying how depressed patients differ in their striatal network during the processing of emotionally salient events is a step towards uncovering biomarkers for diagnosis and treatment. METHODS 38 depressed and 30 healthy adults completed a task that examined brain activation to the anticipation and receipt of monetary rewards and losses. Data were collected using a 3T Siemens Trio scanner. Functional connectivity differences were examined with seeds in the Left or Right VS. FC estimates were regressed on specific symptoms. RESULTS Depressed patients displayed higher functional connectivity between the VS and midline cortical areas during loss versus reward trials. Anhedonia and depressed mood were associated to fairly similar striatal circuits but suicidality was associated to a unique VS-midline structures coupling, while depression severity was linked to higher VS to caudate and precuneus connectivity during loss versus reward trials. CONCLUSIONS Depression is characterized by excessive VS coupling to cognitive control and associative networks during losses versus rewards. High VS to midline cortical structures coupling may index suicidality.

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Depression is associated with negative attention and attribution biases and maladaptive emotion responsivity and regulation, which adversely impact self-evaluations and interpersonal relationships. Using functional magnetic resonance imaging, we investigated the neural substrates of these impairments. We compared neural activity recruited by 126 clinically depressed and healthy adolescents (ages 11–17 years) during social exclusion (Exclusion > Inclusion) using Cyberball. Results revealed significant interaction effects within left anterior insula (AI)/inferior frontal gyrus and left middle temporal gyrus. Insula hyperresponsivity was associated with peer exclusion for depressed adolescents but peer inclusion for healthy adolescents. In additional, healthy adolescents recruited greater lateral temporal activity during peer exclusion. Complementary effect size analyses within independent parcellations offered converging evidence, as well as highlighted medium-to-large effects within subgenual/ventral anterior cingulate cortex and lateral prefrontal, lateral temporal and lateral parietal regions implicated in emotion regulation. Depressogenic neural patterns were associated with negative self-perceptions and negative information processing biases. These findings suggest a neural mechanism underlying cognitive biases in depression, as reflected by emotional hyperresponsivity and maladaptive regulation/reappraisal of negative social evaluative information. This study lends further support for salience and central executive network dysfunction underlying social threat processing, and in particular, highlights the anterior insula as a key region of disturbance in adolescent depression.

The neurophysiology of self-face recognition is altered in adolescent depression. Specifically, depression was associated with decreased activity in neural areas that support emotional and associative processing for positive self-faces and increased processing for neutral self-faces. These results suggest that depression in adolescents is associated with hypoactive emotional processing and encoding of positive self-related visual information. This abnormal neural activity at the intersection of reward and self-processing among depressed youth might have long lasting impact in self-formation and future adult self-representations, given that adolescence is a sensitive period for self-development.

There is limited information regarding the neurobiology underlying non-suicidal self-injury (NSSI) in clinically-referred youth. However, the salience of disturbed interpersonal relationships and disrupted self-processing associated with NSSI suggests the neural basis of social processes as a key area for additional study. Adolescent participants (N=123; M=14.75 years, SD=1.64) were divided into three groups: NSSI plus depression diagnosis (NSSI), depression only (DEP), healthy controls (HC). In the scanner, participants completed an Interpersonal Self-Processing task by taking direct (own) and indirect (mothers’, best friends’, or classmates’) perspectives regarding self-characteristics. Across all perspectives, NSSI showed higher BOLD activation in limbic areas, and anterior and posterior cortical midline structures versus DEP and HC, while HC showed greater activity in rostrolateral, frontal pole and occipital cortex than NSSI and DEP youth. Moreover, NSSI youth showed heightened responses in amygdala, hippocampus, parahippocampus, and fusiform when taking their mothers’ perspective, which were negatively correlated with self-reports of the mother’s support of adolescents’ emotional distress in the NSSI group. NSSI youth also yielded greater precuneus and posterior cingulate cortex activity during indirect self-processing from their classmates’ perspective. Findings suggest a role for disruptions in self- and emotion-processing, and conflicted social relationships in the neurobiology of NSSI among depressed adolescents.