AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors

Abstract

It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit-impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing-dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors.

Figure 1

AgRP neurons determine the behavioral response to novelty and cocaine. (a,b) Exploratory activity (a) and time spent in the center in the open-field test (b) comparing AgRP-Sirt1 (KO) and littermates control mice (CT). (c) Exploratory activity in a different open-field test during 60 min. (d,e) AgRP-Sirt1 mice displayed increased locomotor response to acute cocaine (d) and in a cocaine-sensitization procedure (e) compared with control mice. (f) In the CPP test, AgRP-Sirt1 mice had increased response compared with control mice. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± s.e.m.

Figure 2

AgRP neuronal excitability determines connectivity of VTA dopamine neurons. (a,b) Representative traces, probability plots and average peak amplitude (insets) of miniature postsynaptic currents in control and AgRP-Sirt1 mice. (c) Dose response of GABA blockade on LTP propagation in control. (d) Saturating doses of GABA blockade (10 μM bicuculline (Bic), arrow in c) eliminated mIPSCs in both control and AgRP-Sirt1 mice. (e) AgRP-Sirt1 mice had increased LTP either in the absence of GABA blockade (No) or in the presence of saturating doses of GABA blocker (Sat). (f) Quantification of LTP during development in control and AgRP-Sirt1 mice. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± s.e.m.

Figure 3

AgRP neurons influence the development of VTA dopamine neurons and behavioral responses. (a) The STD-LTP protocol (arrow) was applied in the VTA dopamine cells from control and AgRP neuron–ablated mice. (b,c) Exploratory activity (b) and time in the center in the open field (c) comparing control and AgRP neuron–ablated mice. (d) Exploratory activity in a different open field over 120 min. (e) Locomotor responses of control and AgRP neuron–ablated mice to acute cocaine injections. (f) CPP test for cocaine in a different cohort of mice. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± s.e.m.