IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates

The identification and characterization of multipotent neural precursors open the possibility of transplant therapies, but this approach is complicated by the widespread pathology of many degenerative diseases. Activation of endogenous precursors that support regenerative mechanisms is a possible alternative. We have previously shown that Notch ligands promote stem cell survival in vitro. Here, we show that there is an intimate interaction between insulin and Notch receptor signaling. Notch ligands also expand stem cell numbers in vivo with correlated benefits in brain ischemia. We now show that insulin promotes recovery of injured dopamine neurons in the adult brain. This response suggests that activating survival mechanisms in neural stem cells will promote recovery from progressive degenerative disease.

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“…3a). This is in line with previous reports that the size of dopamine neuron bodies is a measure of their functional strength (Russo et al 2007). …”

Section: Insulin Protects Dopamine Neurons From 6-ohda Toxicitysupporting

confidence: 94%

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Androutsellis-Theotokis¹,

Rueger²,

Mkhikian³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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“…Because of its multiple functions, regulation of IRS2 may be important in the linkages between stress, psychopathology, and the development of associated physiological alterations such as metabolic syndrome and type 2 diabetes. In the periphery, IRS2 regulates insulin sensitivity and in the brain IRS2 impacts multiple functions including reward (58), memory (59,60), and energy homeostasis (61,62). Moreover, type 2 diabetes has been associated with amygdala atrophy (63), and bidirectional associations between insulin resistance and affective disorders have been reported (64)(65)(66).…”

Section: Resultsmentioning

confidence: 99%

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Fox

Oler

Shelton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.positron-emission tomography | microarray | brain imaging T he ability to identify brain mechanisms underlying the risk during childhood for developing anxiety and depression is critical for establishing novel early-life interventions aimed at preventing the chronic and debilitating outcomes associated with these common illnesses. To this end, we have optimized a model of anxious temperament (AT), the conserved at-risk phenotype, in young developing rhesus monkeys (1-4). The rhesus monkey is ideal for studying the origin of human AT because these species share the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning (5-10). Importantly, the rhesus developmental model bridges the critical gap between human psychopathology and rodent models, allowing for translation to humans by using in vivo imaging measures and translation to rodents by using ex vivo molecular methods. Thus, the unique hypotheses that can be generated from the rhesus model are invaluable in guiding both imaging studies in children and mechanistic efforts in rodents.Of particular relevance to the AT rhesus model is the relatively recent evolutionary divergence between rhesus monkeys and humans (25 million years) compared with rodents and humans (70 million years) (5). This evolutionary closeness is reflected in the species' similarities in social and emotional behaviors. These homologies, instantiated in their conserved genetic and neural systems, underlie the ability of both humans and rhesus monkeys to form and maintain the relationships necessary for living in complex social environments. In this regard, the experience of anxiety has evolved in primates to motivate the formation of long-lasting attachment bonds that serve to increase security and group cohesion. The comparable rearing practices shared by these species (e.g., close mother-infant bonding) promote early social/emotional le...

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“…The fact that sensitization is reduced but still significant after quasi-continuous morphine delivery may be related to the 'terminal withdrawal' that occurs following the last morphine injection in each series, as a single morphine injection led to a comparable degree of sensitization as quasi-continuous delivery. The contribution of terminal withdrawal may explain why sensitization is not observed shortly after the termination of chronic drug exposure (Hammer et al, 1997;Russo et al, 2007), but then emerges following a period of abstinence (Aston-Jones and Trujillo et al, 2004). …”

Section: Discussionmentioning

confidence: 99%

“…Sensitization is induced by exposure to most abused drugs, as well as by stressful experience (Kalivas and Stewart, 1991), and is one of the most prominent and thoroughly studied models of long-lasting drug-induced neurobehavioral plasticity. Although tolerance is commonly observed after continuous exposure, sensitization to both the psychomotor-activating and rewarding properties of drugs is most robust following intermittent exposure (Hammer et al, 1997;Hope et al, 2005;King et al, 1992;Nelson and Ellison, 1978;Post, 1980;Reith et al, 1987;Russo et al, 2007;Shippenberg et al, 1988Shippenberg et al, , 1996Shippenberg and Heidbreder, 1995). Despite this extensive evidence, it remains unclear why intermittent drug exposure is so critical for generating sensitization.…”

Section: Introductionmentioning

confidence: 99%

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

Rothwell

Gewirtz

Thomas

2010

Neuropsychopharmacol

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The relative intermittency or continuity of drug delivery is a major determinant of addictive liability, and also influences the impact of drug exposure on brain function and behavior. Events that occur during the offset of drug action (ie, acute withdrawal) may have an important role in the consequences of intermittent drug exposure. We assessed whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization in rodents during daily morphine exposure. The acoustic startle reflexFa measure of anxiety induced by opiate withdrawalFwas used to resolve and quantify discrete withdrawal episodes, and pharmacological interventions were used to manipulate withdrawal severity. Startle potentiation was observed during spontaneous withdrawal from a single morphine exposure, and individual differences in initial withdrawal severity positively predicted the subsequent development of sensitization. Manipulations that reduce or exacerbate withdrawal severity also produced parallel changes in the degree of sensitization. These results demonstrate that the episodic experience of withdrawal during daily drug exposure has a novel role in promoting the development of psychomotor sensitizationFa prominent model of drug-induced neurobehavioral plasticity. Episodic withdrawal may have a pervasive role in many effects of intermittent drug exposure and contribute to the development of addiction.

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IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates

Cited by 190 publications

References 40 publications

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

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