Title Page
Contents
List of publications 10
ABSTRACT 11
Chapter 1. Introduction 13
1.1. Feeding behavior 13
1.1.1. Regulation of feeding behavior 13
1.1.2. Feeding-related peptides 16
1.2. Feeding-related peptides in stress-response 18
1.2.1. Neuropeptide Y 20
1.2.2. Neuropeptide Y in stress responses 22
1.2.3. Cellular mechanism of NPY in stress responses 24
1.2.4. Neuropeptide Y in the lateral habenula 26
1.2.5. Melanocortin 31
1.2.6. Melanocortin system in stress responses 32
1.2.7. Cellular mechanism of the melanocortin system in stress responses 35
1.2.8. Roles of the MC4R in inflammatory stress responses 38
1.2.9. Melanocortin system in the central amygdala 40
1.3. Purpose of study 43
Chapter 2. Actions of NPY on Synaptic Transmission in the LHb 45
2.1. Introduction 45
2.2. Materials and Methods 47
2.2.1. Animals 47
2.2.2. Slice preparation and electrophysiology 47
2.2.3. Data analysis 49
2.3. Results 50
2.3.1. NPY does not alter levels of basal synaptic transmission 50
2.3.2. The excitatory transmission in the LHb is differently affected by NPY application 50
2.3.3. NPY reduces inhibitory transmission onto LHb neurons 51
2.3.4. NPY reduces the spontaneous firing rate of the LHb 52
2.4. Discussion 57
Chapter 3. Protein kinase C mediates neuropeptide Y-induced reduction in inhibitory neurotransmission in the lateral habenula 60
3.1. Introduction 60
3.2. Materials and Methods 62
3.2.1. Animals 62
3.2.2. Slice preparation and electrophysiology 62
3.2.3. Drug 62
3.2.4. Data analysis 63
3.3. Results 64
3.3.1. NPY Y1 receptors mediate the NPY-induced decreases in GABAergic transmission in the LHb 64
3.3.2. NPY modulates GABAergic transmission via a PKA-independent pathway in the LHb 65
3.3.3. PLC/PKC-dependent pathway mediates NPY-induced decrease of GABAergic transmission in the LHb 66
3.4. Discussion 71
Chapter 4. Distinct impact of inflammatory versus psychophysiological stress on brain-wide activation of MC4R-expressing neurons 74
4.1. Introduction 74
4.2. Materials and Methods 76
4.2.1. Animals 76
4.2.2. LPS injection and acute restraint stress procedure 76
4.2.3. Immunohistochemistry 76
4.2.4. Data analysis 77
4.3. Results 78
4.3.1. Both LPS-induced inflammation and restraint stress decrease food intake and body weight 78
4.3.2. LPS injection and restraint stress induce c-Fos expression in non-MC4R+ neurons in the PVN and LS 78
4.3.3. MC4R+ neurons in the ovBNST and the CeA are specifically recruited in LPS-induced inflammation but not in restraint stress 80
4.3.4. The lack of a response in hippocampal c-Fos expression to LPS injection and restraint stress 81
4.4. Discussion 88
Chapter 5. Activation of central amygdala MC4R+ neurons suppresses food consumption 92
5.1. Introduction 92
5.2. Materials and Methods 94
5.2.1. Animals 94
5.2.2. Stereotaxic surgery 94
5.2.3. Acute brain slice preparation 94
5.2.4. Electrophysiology 95
5.2.5. Behavioral procedures 95
5.2.6. Data analysis 96
5.3. Results 97
5.3.1. LPS-induced inflammatory stress selectively increases the excitability of MC4R+ neurons in the CeA 97
5.3.2. LPS-induced inflammation stress enhances inhibitory synaptic transmission in MC4R-neurons in the CeA 98
5.3.3. Chemogenetic activation of MC4R+ neurons in the CeA suppresses feeding behavior 99
5.3.4. Chemogenetic activation of MC4R+ neurons in the CeA does not affect anxiety and depression-like behavior 99
5.3.5. Selective ablation of MC4R+ neurons in the CeA does not prevent the suppression of feeding behavior under LPS-induced inflammation 100
5.4. Discussion 106
Chapter 6. Conclusions 108
References 111
Abstract (in Korean) 138
Figure 2.1. NPY did not alter the spontaneous transmission of LHb neurons. 53
Figure 2.2. NPY differentially modulates excitatory synaptic transmission in the LHb. 54
Figure 2.3. NPY reduced inhibitory synaptic transmission in the LHb. 55
Figure 2.4. NPY did not change basal properties but reduced the spontaneous firing of LHb neurons. 56
Figure 3.1. NPY decreases GABAergic transmission through activation of Y1 receptors in the LHb. 67
Figure 3.2. NPY reduces GABAergic transmission in the LHb independent of PKA. 68
Figure 3.3. The PLC/PKC-dependent pathway mediates NPY-induced decline of GABAergic transmission in the LHb. 69
Figure 3.4. Schematic representation of cellular mechanism by which NPY modulates inhibitory synaptic transmission in the LHb. 70
Figure 4.1. Food intake and body weight were decreased after LPS injection or restraint stress. 82
Figure 4.2. c-Fos+ and MC4R+ neurons after LPS injection or restraint stress in the PVN. 83
Figure 4.3. c-Fos+ and MC4R+ neurons after LPS injection or restraint stress in the LS. 84
Figure 4.4. c-Fos+ and MC4R+ neurons after LPS injection or restraint stress in the BNST. 85
Figure 4.5. c-Fos+ and MC4R+ neurons after LPS injection or restraint stress in the amygdala. 86
Figure 4.6. c-Fos and MC4R expression after LPS injection or restraint stress in the hippocampus. 87
Figure 5.1. Selective increase in excitability of MC4R+ neurons in the CeA upon LPS injection. 101
Figure 5.2. Enhanced inhibitory inputs to MC4R-neurons in the CeA upon inflammatory stress. 102
Figure 5.3. Chemogenetic activation of MC4R+ neurons in the CeA suppressed feeding behavior but had no impact on anxiety-like and depression-like behavior. 103
Figure 5.4. Selective ablation of CeA MC4R+ neurons did not prevent LPS-induced anorexia. 105