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. 2022 Oct 1:217:109201.
doi: 10.1016/j.neuropharm.2022.109201. Epub 2022 Jul 30.

Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens

Nicholas K Smith  1 , Veronika Kondev  1 , Thomas R Hunt  2 , Brad A Grueter  3
Affiliations

Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens

Nicholas K Smith et al. Neuropharmacology. .

Abstract

Social interactions define the human experience, but these integral behaviors are disrupted in many psychiatric disorders. Social behaviors have evolved over millennia, and neuromodulatory systems that promote social behavior in invertebrates are also present in mammalian brains. One such conserved neuromodulator, neuropeptide Y (NPY), acts through several receptors including the Y1r, Y2r, and Y5r. These receptors are present in brain regions that control social behavior, including the nucleus accumbens (NAc). However, whether NPY modulates NAc neurotransmission is unknown. Using whole-cell patch-clamp electrophysiology of NAc neurons, we find that multiple NPY receptors regulate excitatory synaptic transmission in a cell-type specific manner. At excitatory synapses onto D1+ MSNs, Y1r activity enhances transmission while Y2r suppresses transmission. At excitatory synapses onto D1- MSNs, Y5r activity enhances transmission while Y2r suppresses transmission. Directly infusing NPY or the Y1r agonist [Leu31, Pro34]-NPY into the NAc significantly increases social interaction with an unfamiliar conspecific. Inhibition of an enzyme that breaks down NPY, dipeptidyl peptidase IV (DPP-IV), shifts the effect of NPY on D1+ MSNs to a Y1r dominated phenotype. Together, these results increase our understanding of how NPY regulates neurotransmission in the NAc and identify a novel mechanism underlying the control of social behavior. Further, they reveal a potential strategy to shift NPY signaling for therapeutic gain.

Keywords: Dipeptidyl peptidase IV; Excitatory synaptic transmission; Glutamate; Neuropeptide Y; Nucleus accumbens; Social interaction.

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Conflict of interest statement

Declaration of competing interest

Authors declare no competing interests.

Figures

Fig. 1. |
Fig. 1. |
Excitatory synaptic transmission onto D1+ MSNs is enhanced by the Y1r agonist [Leu31, Pro34]-NPY and depressed by the Y2r agonist PYY (3–36). (A) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after NPY application. Second trace corresponds to shaded area in time course graph. (B) Average EPSC amplitude in D1+ MSNs following NPY application (n = 7 cells from 5 mice). (C) NPY application does not change average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline (D) NPY application does not change average PPR (shaded area) in D1+ MSNs compared to baseline. (E) NPY application does not change average CV (shaded area) in D1+ MSNs compared to baseline. (F) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after [Leu31, Pro34]-NPY application. Second trace corresponds to shaded area in time course graph. (G) Average EPSC amplitude in D1+ MSNs following [Leu31, Pro34]-NPY application (n = 7 cells from 5 mice). (H) [Leu31, Pro34]-NPY application increases average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline. (I) [Leu31, Pro34]-NPY application decreases average PPR (shaded area) in D1+ MSNs compared to baseline. (J) [Leu31, Pro34]-NPY application does not change average CV (shaded area) in D1+ MSNs compared to baseline. (K) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after PYY (3–36). Second trace corresponds to shaded area in time course graph. (L) Average EPSC amplitude in D1+ MSNs following PYY (3–36) application (n = 8 from 4 mice). (M) PYY (3–36) application decreases average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline. (N) PYY (3–36) application does not change average PPR (shaded area) in D1+ MSNs compared to baseline. (O) PYY (3–36) application does not change average CV (shaded area) in D1+ MSNs compared to baseline. (P) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after hPP application. Second trace corresponds to shaded area in time course graph. (Q) Average EPSC amplitude in D1+ MSNs following hPP application (n = 6 from 4 mice). (R) hPP application does not change average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline. (S) hPP application does not change average PPR (shaded area) in D1+ MSNs compared to baseline. (T) hPP application does not change average CV (shaded area) in D1+ MSNs compared to baseline. *p < 0.05, **p < 0.01.
Fig. 2. |
Fig. 2. |
[Leu31, Pro34]-NPY mediated enhancement of excitatory synaptic transmission onto D1+ MSNs requires Y1r, and PYY (3–36) mediated depression of excitatory synaptic transmission onto D1+ MSNs requires Y2r. (A) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after [Leu31, Pro34]-NPY application in the presence of BIBO 3304. Second trace corresponds to shaded area in time course graph. (B) Average EPSC amplitude in D1+ MSNs following [Leu31, Pro34]-NPY application in the presence of BIBO 3304 (n = 5 from 4 mice). (C) [Leu31, Pro34]-NPY application does not change average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline in the presence of BIBO 3304. (D) [Leu31, Pro34]-NPY application does not change average PPR (shaded area) in D1+ MSNs compared to baseline in the presence of BIBO 3304. (E) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after PYY (3–36) application in the presence of BIIE 0246. Second trace corresponds to shaded area in time course graph. (F) Average EPSC amplitude in D1+ MSNs following PYY (3–36) application in the presence of BIIE 0246 (n = 5 from 3 mice). (G) PYY (3–36) application does not change average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline in the presence of BIIE 0246. *p < 0.05.
Fig. 3. |
Fig. 3. |
Excitatory synaptic transmission onto D1− MSNs is depressed by the Y2r agonist PYY (3–36) and enhanced by Y5r agonist hPP. (A) Representative traces of EPSC amplitude recorded from a D1− MSN before and after NPY application. Second trace corresponds to shaded area in time course graph. (B) Average EPSC amplitude in D1− MSNs following NPY application (n = 7 from 6 mice). (C) NPY application does not change average EPSC amplitude (shaded area) in D1− MSNs compared to baseline. (D) NPY application does not change average PPR (shaded area) in D1− MSNs compared to baseline. (E) NPY application does not change average CV (shaded area) in D1− MSNs compared to baseline. (F) Representative traces of EPSC amplitude recorded from a D1− MSN before and after [Leu31, Pro34]-NPY application. Second trace corresponds to shaded area in time course graph. (G) Average EPSC amplitude in D1− MSNs following [Leu31, Pro34]-NPY application (n = 7 from 6 mice). (H) [Leu31, Pro34]-NPY application does not change average EPSC amplitude (shaded area) in D1− MSNs compared to baseline. (I) [Leu31, Pro34]-NPY application does not change average PPR (shaded area) in D1− MSNs compared to baseline. (J) [Leu31, Pro34]-NPY application does not change average CV (shaded area) in D1− MSNs compared to baseline. (K) Representative traces of EPSC amplitude recorded from a D1− MSN before and after PYY (3–36) application. Second trace corresponds to shaded area in time course graph. (L) Average EPSC amplitude in D1− MSNs following PYY (3–36) application (n = 7 from 6 mice). (M) PYY (3–36) application decreases average EPSC amplitude (shaded area) in D1− MSNs compared to baseline. (N) PYY (3–36) application does not change average PPR (shaded area) in D1− MSNs compared to baseline. (O) PYY (3–36) application does not change average CV (shaded area) in D1− MSNs compared to baseline. (P) Representative traces of EPSC amplitude recorded from a D1− MSN before and after hPP application. Second trace corresponds to shaded area in time course graph. (Q) Average EPSC amplitude in D1− MSNs following hPP application (n = 9 from 7 mice). (R) hPP application increases average EPSC amplitude (shaded area) in D1− MSNs compared to baseline. (S) hPP application decreases average PPR (shaded area) in D1− MSNs compared to baseline. (T) hPP application decreases average CV (shaded area) in D1− MSNs compared to baseline. *p < 0.05.
Fig. 4. |
Fig. 4. |
PYY (3–36) mediated decrease in EPSC amplitude onto D1 – MSNs requires Y2r and hPP mediated enhancement in EPSC amplitude onto D1− MSNs requires Y5r. (A) Representative traces of EPSC amplitude recorded from a D1− MSN before and after PYY (3–36) application. Second trace corresponds to shaded area in time course graph. (B) Average EPSC amplitude in D1− MSNs following PYY (3–36) application in the presence of BIIE 0246 (n = 5 from 3 mice). (C) PYY (3–36) application does not change average EPSC amplitude (shaded area) compared to baseline in the presence of BIIE 0246. (D) Representative traces of EPSC amplitude recorded from a D1− MSN before and after hPP application. Second trace corresponds to shaded area in time course graph. (E) Average EPSC amplitude in D1− MSNs following hPP application in the presence of L-152,804 (n = 5 from 3 mice). (F) hPP application does not change average EPSC amplitude (shaded area) compared to baseline in the presence of L-152,804. (G) hPP application does not change average PPR (shaded area) compared to baseline in the presence of L-152,804.
Fig. 5. |
Fig. 5. |
Intra-NAc NPY and [Leu31, Pro34]-NPY enhance social interaction time with an unfamiliar conspecific. (A) Diagram of identified cannula termination sites. (B) Diagram of three chamber social interaction assay, created with BioRender. (C) Intra-NAc NPY increases distance traveled in the pretest period (n = 7 mice). (D) Intra-NAc NPY increases interaction time with the social stimulus relative to vehicle treatment but does not increase interaction time with the non-social stimulus. (E) Intra-NAc NPY increases the average size of an interaction bout with the social stimulus relative to vehicle treatment but does not increase the average size of an interaction bout with the non-social stimulus. (F) Intra-NAc [Leu31, Pro34]-NPY does not alter the distance traveled during the pretest period (n = 7 mice). (G) Intra-NAc [Leu31, Pro34]-NPY increases interaction time with the social stimulus relative to vehicle treatment but does not increase interaction time with the non-social stimulus. (H) Intra-NAc [Leu31, Pro34]-NPY increases the average size of an interaction bout with the social stimulus relative to vehicle treatment but does not increase the average size of an interaction bout with the non-social stimulus. *p < 0.05, **p < 0.01, ***p < 0.001.
Fig. 6. |
Fig. 6. |
Inhibition of DPP-IV with sitagliptin results in a Y1r mediated enhancement of EPSC amplitude in D1+ MSNs following NPY application. (A) Diagram depicting DPP-IV mediated breakdown of NPY, producing NPY (3–36) which exhibits higher affinity for Y2r and Y5r over Y1r. DPP-IV is inhibited by the FDA approved inhibitor sitagliptin. (B) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after sitagliptin application. Second trace corresponds to shaded area in time course graph. (C) Average EPSC amplitude in D1+ MSNs following sitagliptin application (n = 7 from 5 mice). (D) Sitagliptin application does not change average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline. (E) Representative traces of EPSC amplitude recorded from a D1− MSN before and after NPY application in the presence of sitagliptin. Second trace corresponds to shaded area in time course graph. (F) Average EPSC amplitude in D1+ MSNs following NPY application in the presence of sitagliptin (n = 10 from 8 mice) (G) NPY application increases average EPSC amplitude (shaded area) in D1+ MSNs compared to baseline in the presence of sitagliptin. (H) NPY application decreases average PPR (shaded area) in D1+ MSNs compared to baseline in the presence of sitagliptin. (I) NPY application does not change average CV (shaded area) in D1+ MSNs compared to baseline in the presence of sitagliptin. (J) Representative traces of EPSC amplitude recorded from a D1+ MSN before and after NPY application in the presence of sitagliptin and BIBO 3304. Second trace corresponds to shaded area in time course graph. (K) Average EPSC amplitude in D1+ MSNs following NPY application in the presence of sitagliptin and BIBO 3304 (n = 6 from 5 mice). (L) NPY application does not change average EPSC amplitude (shaded area) in D1+ MSNs in the presence of both sitagliptin and BIBO 3304. (M) NPY application does not change average PPR (shaded area) in D1+ MSNs in the presence of both sitagliptin and BIBO 3304. (N) NPY application does not change average CV (shaded area) in D1+ MSNs in the presence of both sitagliptin and BIBO 3304. *p < 0.05.
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