Insulin Bidirectionally Alters NAc Glutamatergic Transmission: Interactions between Insulin Receptor Activation, Endogenous Opioids, and Glutamate Release
| Autor: | Carrie R. Ferrario, Max F. Oginsky, Zuleirys Santana-Rodriguez, Tracy L. Fetterly, Yanaira Alonso-Caraballo, Allison M. Nieto |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Patch-Clamp Techniques nucleus accumbens medicine.medical_treatment Presynaptic Terminals Glutamic Acid glutamate Medium spiny neuron Diet High-Fat Synaptic Transmission Receptor IGF Type 1 Rats Sprague-Dawley 03 medical and health sciences Glutamatergic 0302 clinical medicine motivation Postsynaptic potential Internal medicine medicine Animals Insulin Obesity insulin receptor Research Articles Endogenous opioid Neurons biology Chemistry Receptors Dopamine D2 General Neuroscience Receptors Dopamine D1 Glutamate receptor Receptor Insulin Rats Insulin receptor 030104 developmental biology Endocrinology Excitatory postsynaptic potential biology.protein opioid Endorphins striatal plasticity 030217 neurology & neurosurgery Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Furthermore, insulin dysregulation accompanying obesity is linked to cognitive decline, depression, anxiety, and altered motivation that rely on NAc excitatory transmission. Using whole-cell patch-clamp and biochemical approaches, we determined how insulin affects NAc glutamatergic transmission in nonobese and obese male rats and the underlying mechanisms. We find that there are concentration-dependent, bidirectional effects of insulin on excitatory transmission, with insulin receptor activation increasing and IGF receptor activation decreasing NAc excitatory transmission. Increases in excitatory transmission were mediated by activation of postsynaptic insulin receptors located on MSNs. However, this effect was due to an increase in presynaptic glutamate release. This suggested feedback from MSNs to presynaptic terminals. In additional experiments, we found that insulin-induced increases in presynaptic glutamate release are mediated by opioid receptor-dependent disinhibition. Furthermore, obesity resulted in a loss of insulin receptor-mediated increases in excitatory transmission and a reduction in NAc insulin receptor surface expression, while preserving reductions in transmission mediated by IGF receptors. These results provide the first insights into how insulin influences excitatory transmission in the adult brain, and evidence for a previously unidentified form of opioid receptor-dependent disinhibition of NAc glutamatergic transmission. SIGNIFICANCE STATEMENT Data here provide the first insights into how insulin influences excitatory transmission in the adult brain, and identify previously unknown interactions between insulin receptor activation, opioids, and glutamatergic transmission. These data contribute to our fundamental understanding of insulin's influence on brain motivational systems and have implications for the use of insulin as a cognitive enhancer and for targeting of insulin receptors and IGF receptors to alter motivation. |
| Databáze: | OpenAIRE |
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