Contrast reversal of the iris and sclera increases the face sensitive N170.

Previous research has demonstrated that reversing the contrast of the eye region, which includes the eyebrows, affects the N170 ERP. To selectively assess the impact of just the eyes, the present study evaluated the N170 in response to reversing contrast polarity of just the iris and sclera in upright and inverted face stimuli. Contrast reversal of the eyes increased the amplitude of the N170 for upright faces, but not for inverted faces, suggesting that the contrast of eyes is an important contributor to the N170 ERP.

The independent detection of motion energy and counterchange: flexibility in motion detection.

Motion perception is determined by changing patterns of neural activation initiated by spatiotemporal changes in stimulus features. Motion specified by 1st-order motion energy entails neural patterns that are initiated by spatiotemporal changes in luminance, whereas motion specified by counterchange entails oppositely signed changes in neural activation that can be initiated by spatiotemporal changes in any feature. A constraint in furthering this distinction is that motion energy and counterchange are co-specified by most visual stimuli. In the current study, counterchange was isolated for stimuli composed of translating subjective (Kanizsa) squares, surfaces created by the visual system. Motion energy was isolated for stimuli composed of sequences of luminance increments that spread across perceptually stationary, literal surfaces. Counterchange-specified motion was perceived over a wide range of frame durations, and preferentially for short motion paths. Motion specified by motion energy was diminished for relatively long frame durations, and was unaffected by the length of the motion path. Finally, it was found that blank inter-frame intervals can restore counterchange-specified motion perception for frame durations that are otherwise too brief for motion to be perceived. The results of these and earlier experiments suggest that 1st-order motion energy mechanisms, dedicated to the detection of changes in neural activation initiated by spatiotemporal changes in luminance, provide the basis for objectless motion perception (Wertheimer's phi motion). In contrast, counterchanging neural activation initiated by spatiotemporal changes in any feature, including features created by the visual system, provides a flexible basis for the perception of object motion (Wertheimer's beta motion).

Dorsal stream activity and connectivity associated with action priming of ambiguous apparent motion.

Theories proposing a bidirectional influence between action and perception are well supported by behavioral findings. In contrast to the growing literature investigating the brain mechanisms by which perception influences action, there is a relative dearth of neural evidence documenting how action may influence perception. Here we show that action priming of apparent motion perception is associated with increased functional connectivity between dorsal cortical regions connecting vision with action. Participants manually rotated a joystick in a clockwise or counter-clockwise direction while viewing ambiguous apparent rotational motion. Actions influenced perception when the perceived direction of the ambiguous display was the same as manual rotation. For comparison, participants also rotated the joystick while viewing non-ambiguous apparent motion and in the absence of apparent motion. In a final control condition, participants viewed ambiguous apparent motion without manual rotation. Actions influence on perception was accompanied by a significant increase in alpha and beta band event related desynchronization (ERD) in contralateral primary motor cortex, superior parietal lobe and middle occipital gyrus. Increased ERD across these areas was accompanied by an increase in gamma band phase locking between primary motor, parietal, striate and extrastriate regions. Similar patterns were not observed when action was compatible with perception, but did not influence it. These data demonstrate that action influences perception by strengthening the interaction across a broad sensorimotor network for the putative purpose of integrating compatible action outcomes and sensory information into a single coherent percept.

Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle -insight from analysis of a transgenic mouse model-.

To examine the role of muscle AMP-activated protein kinase (AMPK) in maximal exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle, we generated muscle-specific transgenic mice carrying cDNAs of inactive AMPK alpha2 (alpha2i TG). Fed blood glucose was slightly higher in alpha2i TG mice compared to wild type littermates, however, the difference was not statistically significant. In alpha2i TG mice, glucose tolerance was slightly impaired in male, but not in female mice, compared to wild type littermates. Maximal exercise capacity was dramatically reduced in alpha2i TG mice, suggesting that AMPK alpha2 has a critical role in skeletal muscle during exercise. We confirmed that known insulin-independent stimuli of glucose transport including mitochondrial respiration inhibition, hyperosmolarity, and muscle contraction increased both AMPK alpha1 and alpha2 activities in isolated EDL muscle in wild type mice. While, alpha2 activation was severely blunted and alpha1 activation was only slightly reduced in alpha2i TG mice by these insulin independent stimuli compared to wild type mice. Mitochondrial respiration inhibition-induced glucose transport was fully inhibited in isolated EDL muscles in alpha2i TG mice. However, contraction- or hyperosmolarity-induced glucose transport was nearly normal. These results suggest that AMPK alpha2 activation is essential for some, but not all insulin-independent glucose transport.

AMP-activated protein kinase alpha2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle.

To examine the role of AMP-activated protein kinase (AMPK) in muscle glucose transport, we generated muscle-specific transgenic mice (TG) carrying cDNAs of inactive alpha2 (alpha2i TG) and alpha1 (alpha1i TG) catalytic subunits. Extensor digitorum longus (EDL) muscles from wild type and TG mice were isolated and subjected to a series of in vitro incubation experiments. In alpha2i TG mice basal alpha2 activity was barely detectable, whereas basal alpha1 activity was only partially reduced. Known AMPK stimuli including 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), rotenone (a Complex I inhibitor), dinitrophenol (a mitochondrial uncoupler), muscle contraction, and sorbitol (producing hyperosmolar shock) did not increase AMPK alpha2 activity in alpha2i TG mice, whereas alpha1 activation was attenuated by only 30-50%. Glucose transport was measured in vitro using isolated EDL muscles from alpha2i TG mice. AICAR- and rotenone-stimulated glucose transport was fully inhibited in alpha2i TG mice; however, the lack of AMPK alpha2 activity had no effect on contraction- or sorbitol-induced glucose transport. Similar to these observations in vitro, contraction-stimulated glucose transport, assessed in vivo by 2-deoxy-d-[(3)H]glucose incorporation into EDL, tibialis anterior, and gastrocnemius muscles, was normal in alpha2i TG mice. Thus, AMPK alpha2 activation is essential for some, but not all, insulin-independent glucose transport. Muscle contraction- and hyperosmolarity-induced glucose transport may be regulated by a redundant mechanism in which AMPK alpha2 is one of multiple signaling pathways.

Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis.

Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.

Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3.

Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin.

Secretion of leptin from adipose tissue communicates body energy status to the neuroendocrine system by activating the long form of the leptin receptor (LRb). Lack of leptin or LRb (as in db/db mice) results in obesity that stems from the combined effects of hyperphagia and decreased energy expenditure. We have previously generated mice in which LRb is replaced with a mutant LRb (LRbS1138) that specifically disrupts LRb-->STAT3 (signal transducer and activator of transcription-3) signaling; mice homozygous for this mutant (s/s) display increased feeding and are obese. We have now examined energy expenditure in s/s and db/db mice. Consistent with the increased lean body mass of s/s animals, locomotor activity and acute cold tolerance (partly a measure of shivering thermogenesis) in s/s mice were modestly but significantly improved compared with db/db mice, although they were decreased compared with wild-type mice. Total and resting metabolic rates were similarly depressed in s/s and db/db mice, however. Indeed, s/s and db/db mice display similar reductions in thyroid function and brown adipose tissue expression of uncoupling protein-1, which is regulated by sympathetic nervous system (SNS) tone. Thus, the LRb-->STAT3 signal is central to both the control of energy expenditure by leptin and the neuroendocrine regulation of the SNS and the thyroid axis.