Insulin Bidirectionally Alters NAc Glutamatergic Transmission: Interactions between Insulin Receptor Activation, Endogenous Opioids, and Glutamate Release

Abstract

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 pre-synaptic and post-synaptic 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 aberrant motivation that rely on NAc excitatory transmission. Using whole-cell patch clamp and biochemical approaches we determined how insulin affects NAc glutamatergic transmission in non-obese and obese male rats and the underlying mechanisms. We find that there are concentration-dependent, bi-directional effects of insulin on excitatory transmission, with insulin receptor activation increasing and IGF receptor activation decreasing NAc excitatory transmission. Increases in 2 2 excitatory transmission were mediated by activation of post-synaptic 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. Introduction:Recent studies in humans suggest that insulin may enhance cognition and decision-making processes that

Insulin and endocannabinoids in the mesolimbic system

“…Insulin receptors and Akt pathways in the NAc can be stimulated within 7 minutes of glucose ingestion, 62 suggesting that peripheral insulin can rapidly cross the blood-brain barrier and influence striatal function. Similarly, insulin-induced enhancement of glutamate release onto MSNs occurred early after insulin application to NAc slices, 55 whereas insulin-induced suppression of excitatory inputs onto dopaminergic neurones in VTA was at its greatest 15-25 minutes after insulin application. 47 It is unclear how rapidly NAc DA increases after prolonged insulin application because the study did not present a time course of effect.…”

“…At low nanomolar, presumably physiological concentrations, insulin increases the firing rate of cholinergic neurones in the Nac, leading to increased cholinergic activation of nicotinic receptors at dopamine terminals and enhancing dopamine release in striatal slices 54 (Figure 1C). Furthermore, insulin has bidirectional effects at excitatory synapses in the NAc dependent on concentration 55 (Figure 1C). Supraphysiological concentrations target presynaptic insulin-like growth factor (IGF)1 receptors to suppress glutamate release onto MSNs, whereas low nanomolar insulin concentrations target insulin receptors on MSNs to increase glutamate release onto MSNs via a previously unidentified retrograde opioid receptor-mediated form of disinhibition.…”

“…Insulin receptors are expressed on cholinergic neurones, 54 MSNs 55 and glial cells 42 within the NAc. At low nanomolar, presumably physiological concentrations, insulin increases the firing rate of cholinergic neurones in the Nac, leading to increased cholinergic activation of nicotinic receptors at dopamine terminals and enhancing dopamine release in striatal slices 54 (Figure 1C).…”

“…Supraphysiological concentrations target presynaptic insulin-like growth factor (IGF)1 receptors to suppress glutamate release onto MSNs, whereas low nanomolar insulin concentrations target insulin receptors on MSNs to increase glutamate release onto MSNs via a previously unidentified retrograde opioid receptor-mediated form of disinhibition. 55 Interestingly, IGF1 can be released from dopamine neurones following depolarisation and can act somatodendritically to suppress firing, as well as at terminals to influence striatal dopamine concentration. 56 Thus, both IGF1 and insulin can modulate dopamine release, firing and synaptic transmission in the striatum (Figure 1).…”

“…54 Furthermore, diet-induced obesity results in a loss of insulinmediated potentiation of glutamatergic synaptic transmission, likely as a result of a down-regulation of insulin receptor expression. 55 Thus, insulin modulation of striatal function may be dependent on energy availability and/or energy reserves.…”