Significance

The neuropeptide system encompasses the most diverse family of neurotransmitters, but their expression, cellular localization, and functional role in the human brain have received limited attention. Here, we study human postmortem samples from prefrontal cortex (PFC), a key brain region, and employ RNA sequencing and RNAscope methods integrated with published single-cell data. Our aim is to characterize the distribution of peptides and their receptors in 17 PFC subregions and to explore their role in chemical signaling. The results suggest that the well-established anatomical and functional heterogeneity of human PFC is also reflected in the expression pattern of the neuropeptides. Our findings support ongoing efforts from academia and pharmaceutical companies to explore the potential of neuropeptide receptors as targets for drug development.

Abstract

Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter–related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine–regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.

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Data Availability

The transcriptomics data reported in this article for the 17 human prefrontal cortex subregions and 3 reference cortical regions (frontal, parietal, and temporal cortex), gene information, and normalized TPM values are available, open-access, and downloadable from the Human Protein Atlas database (https://www.proteinatlas.org/about/download) (53).
All data are included in the article and/or supporting information.

Acknowledgments

We thank Drs. S. Paabo (Ref. 63), E. Lein (Ref. 64) and L.H. Tsai (Ref. 71) for allowing us to use their results—they have been essential for our study. We thank Mattias Karlén for two excellent drawings (Figs. 6 and 7). We appreciate valuable advice and input from Dr. Huda Zoghbi, as well as from Drs. Rainer Landgraf, Mike Ludwig, Ming Zhao, Zhi-Qing David Xu, Tibor Harkany, and Nolan Williams. We thank Magdolna Toronyay-Kasztner for managing the HBTB database and acknowledge support from the National Genomics Infrastructure in Stockholm funded by the Science for Life Laboratory, Knut and Alice Wallenberg Foundation and the Swedish National Infrastructure for Computing (SNIC)/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We thank the Knut and Alice Wallenberg Foundation, Swedish Research Council (2018-02753 and 2020-02956), SciLifeLab and Wallenberg Data Driven Life Science Program (Grant KAW 2020.0239), and Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002) for financial support.

Supporting Information

Appendix 01 (PDF)
Dataset S01 (XLSX)
Dataset S02 (XLSX)
Dataset S03 (XLSX)
Dataset S04 (XLSX)
Dataset S05 (XLSX)
Dataset S06 (XLSX)
Dataset S07 (XLSX)
Dataset S08 (XLSX)

References

1
J. Fuster, The Prefrontal Cortex (Academic Press, 2015).
2
M. L. Dixon, R. Thiruchselvam, R. Todd, K. Christoff, Emotion and the prefrontal cortex: An integrative review. Psychol. Bull. 143, 1033–1081 (2017).
3
J. L. Price, W. C. Drevets, Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).
4
D. H. Ingvar, G. Franzén, Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr. Scand. 50, 425–462 (1974).
5
K. F. Berman, D. R. Weinberger, The prefrontal cortex in schizophrenia and other neuropsychiatric diseases: In vivo physiological correlates of cognitive deficits. Prog. Brain Res. 85, 521–536, discussion 536–537 (1990).
6
P. S. Goldman-Rakic, The physiological approach: Functional architecture of working memory and disordered cognition in schizophrenia. Biol. Psychiatry 46, 650–661 (1999).
7
E. L. Belleau, M. T. Treadway, D. A. Pizzagalli, The impact of stress and major depressive disorder on hippocampal and medial prefrontal cortex morphology. Biol. Psychiatry 85, 443–453 (2019).
8
B. Vogt, Cingulate Neurobiology and Disease (Oxford University Press, 2009).
9
E. T. Rolls, The orbitofrontal cortex and emotion in health and disease, including depression. Neuropsychologia 128, 14–43 (2019).
10
T. W. Robbins, A. F. Arnsten, The neuropsychopharmacology of fronto-executive function: Monoaminergic modulation. Annu. Rev. Neurosci. 32, 267–287 (2009).
11
B. J. Everitt, T. W. Robbins, Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).
12
N. D. Volkow, J. S. Fowler, G. J. Wang, The addicted human brain viewed in the light of imaging studies: Brain circuits and treatment strategies. Neuropharmacology 47 (suppl. 1), 3–13 (2004).
13
N. R. Osborne et al., Abnormal subgenual anterior cingulate circuitry is unique to women but not men with chronic pain. Pain 162, 97–108 (2021).
14
B. A. Vogt, R. W. Sikes, “Cingulate nociceptive circuitry and roles in pain processing: The cingulate premotor pain model” in Cingulate Neurobiology and Disease, B. A. Vogt, Ed. (Oxford University Press, 2009), pp. 312–339.
15
D. de Wied, The neuropeptide concept. Prog. Brain Res. 72, 93–108 (1987).
16
J. P. H. Burbach, Neuropeptides from concept to online database www.neuropeptides.nl. Eur. J. Pharmacol. 626, 27–48 (2010).
17
A. Kastin, Handbook of Biologically Active Peptides (Academic Press, 2013).
18
J. DeFelipe, Neocortical neuronal diversity: Chemical heterogeneity revealed by colocalization studies of classic neurotransmitters, neuropeptides, calcium-binding proteins, and cell surface molecules. Cereb. Cortex 3, 273–289 (1993).
19
J. DeFelipe et al., New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 14, 202–216 (2013).
20
C. Bouras, P. J. Magistretti, J. H. Morrison, An immunohistochemical study of six biologically active peptides in the human brain. Hum. Neurobiol. 5, 213–226 (1986).
21
E. Braak, H. Braak, A. Weindl, Somatostatin-like immunoreactivity in non-pyramidal neurons of the human isocortex. Anat. Embryol. (Berl.) 173, 237–246 (1985).
22
V. Chan-Palay, Y. S. Allen, W. Lang, U. Haesler, J. M. Polak, Cytology and distribution in normal human cerebral cortex of neurons immunoreactive with antisera against neuropeptide Y. J. Comp. Neurol. 238, 382–389 (1985).
23
S. R. Vincent et al., Neuropeptide coexistence in human cortical neurones. Nature 298, 65–67 (1982).
24
J. P. Hornung, N. De Tribolet, I. Törk, Morphology and distribution of neuropeptide-containing neurons in human cerebral cortex. Neuroscience 51, 363–375 (1992).
25
S. M. Sagar, M. F. Beal, P. E. Marshall, D. M. Landis, J. B. Martin, Implications of neuropeptides in neurological diseases. Peptides 5 (suppl. 1), 255–262 (1984).
26
H. Taquet et al., Biochemical mapping of cholecystokinin-, substance P-, [Met]enkephalin-, [Leu]enkephalin- and dynorphin A (1-8)-like immunoreactivities in the human cerebral cortex. Neuroscience 27, 871–883 (1988).
27
D. F. Brockway, N. A. Crowley, Turning the ’tides on neuropsychiatric diseases: The role of peptides in the prefrontal cortex. Front. Behav. Neurosci. 14, 588400 (2020).
28
C. Fee, M. Banasr, E. Sibille, Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: Cortical microcircuit and therapeutic perspectives. Biol. Psychiatry 82, 549–559 (2017).
29
H. M. Morris, T. Hashimoto, D. A. Lewis, Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder. Cereb. Cortex 18, 1575–1587 (2008).
30
M. Beneyto, H. M. Morris, K. C. Rovensky, D. A. Lewis, Lamina- and cell-specific alterations in cortical somatostatin receptor 2 mRNA expression in schizophrenia. Neuropharmacology 62, 1598–1605 (2012).
31
S. J. Fung et al., Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am. J. Psychiatry 167, 1479–1488 (2010).
32
L. Caberlotto, Y. L. Hurd, Neuropeptide Y Y(1) and Y(2) receptor mRNA expression in the prefrontal cortex of psychiatric subjects. Relationship of Y(2) subtype to suicidal behavior. Neuropsychopharmacology 25, 91–97 (2001).
33
A. Tripp, R. S. Kota, D. A. Lewis, E. Sibille, Reduced somatostatin in subgenual anterior cingulate cortex in major depression. Neurobiol. Dis. 42, 116–124 (2011).
34
E. Sibille, H. M. Morris, R. S. Kota, D. A. Lewis, GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. Int. J. Neuropsychopharmacol. 14, 721–734 (2011).
35
R. C. Kessler, Epidemiology of women and depression. J. Affect. Disord. 74, 5–13 (2003).
36
A. V. Seligowski, N. G. Harnett, J. B. Merker, K. J. Ressler, Nervous and endocrine system dysfunction in posttraumatic stress disorder: An overview and consideration of sex as a biological variable. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 5, 381–391 (2020).
37
M. L. Seney, J. Glausier, E. Sibille, Large-scale transcriptomics studies provide insight into sex differences in depression. Biol. Psychiatry 91, 14–24 (2022).
38
G. Juhasz et al., Brain galanin system genes interact with life stresses in depression-related phenotypes. Proc. Natl. Acad. Sci. U.S.A. 111, E1666–E1673 (2014).
39
S. Barde et al., Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide. Proc. Natl. Acad. Sci. U.S.A. 113, E8472–E8481 (2016).
40
C. J. Grimmelikhuijzen, F. Hauser, Mini-review: The evolution of neuropeptide signaling. Regul. Pept. 177, S6–S9 (2012).
41
A. N. van den Pol, Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).
42
M. P. Nusbaum, D. M. Blitz, E. Marder, Functional consequences of neuropeptide and small-molecule co-transmission. Nat. Rev. Neurosci. 18, 389–403 (2017).
43
C. I. Bargmann, Beyond the connectome: How neuromodulators shape neural circuits. BioEssays 34, 458–465 (2012).
44
T. Hökfelt et al., Neuropeptide and small transmitter coexistence: Fundamental studies and relevance to mental illness. Front. Neural Circuits 12, 106 (2018).
45
J. M. Lundberg, T. Hökfelt, Coexistence of peptides and classical neurotransmitters. Trends Neurosci. 6, 325–333 (1983).
46
T. Bartfai, K. Iverfeldt, G. Fisone, P. Serfözö, Regulation of the release of coexisting neurotransmitters. Annu. Rev. Pharmacol. Toxicol. 28, 285–310 (1988).
47
C. A. Bondy, H. Gainer, J. T. Russell, Effects of stimulus frequency and potassium channel blockade on the secretion of vasopressin and oxytocin from the neurohypophysis. Neuroendocrinology 46, 258–267 (1987).
48
M. Verhage, W. E. Ghijsen, F. H. Lopes da Silva, Presynaptic plasticity: The regulation of Ca(2+)-dependent transmitter release. Prog. Neurobiol. 42, 539–574 (1994).
49
M. C. C. Guillaumin, D. Burdakov, Neuropeptides as primary mediators of brain circuit connectivity. Front. Neurosci. 15, 644313 (2021).
50
T. Hökfelt, O. Johansson, A. Ljungdahl, J. M. Lundberg, M. Schultzberg, Peptidergic neurones. Nature 284, 515–521 (1980).
51
S. H. Hendry et al., Neuropeptide-containing neurons of the cerebral cortex are also GABAergic. Proc. Natl. Acad. Sci. U.S.A. 81, 6526–6530 (1984).
52
P. Somogyi et al., Different populations of GABAergic neurons in the visual cortex and hippocampus of cat contain somatostatin- or cholecystokinin-immunoreactive material. J. Neurosci. 4, 2590–2603 (1984).
53
The Brain Atlas. The Human Protein Atlas. https://v20.proteinatlas.org/humanproteome/brain. Accessed 26 July 2022.
54
N. G. Seidah, M. Chrétien, Proprotein and prohormone convertases: A family of subtilases generating diverse bioactive polypeptides. Brain Res. 848, 45–62 (1999).
55
L. Jackson, W. Eldahshan, S. C. Fagan, A. Ergul, Within the brain: The renin angiotensin system. Int. J. Mol. Sci. 19, 876 (2018).
56
J. Dai, C. Patzke, K. Liakath-Ali, E. Seigneur, T. C. Südhof, GluD1 is a signal transduction device disguised as an ionotropic receptor. Nature 595, 261–265 (2021).
57
K. Matsuda et al., Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 328, 363–368 (2010).
58
M. Shibata et al., Hominini-specific regulation of CBLN2 increases prefrontal spinogenesis. Nature 598, 489–494 (2021).
59
J. M. Burgunder, W. S. Young III, The distribution of thalamic projection neurons containing cholecystokinin messenger RNA, using in situ hybridization histochemistry and retrograde labeling. Brain Res. 464, 179–189 (1988).
60
L. M. McLatchie et al., RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998).
61
A. S. Carlo, A. Nykjaer, T. E. Willnow, Sorting receptor sortilin—A culprit in cardiovascular and neurological diseases. J. Mol. Med. (Berl.) 92, 905–911 (2014).
62
S. J. Smith et al., Single-cell transcriptomic evidence for dense intracortical neuropeptide networks. eLife 8, e47889 (2019).
63
E. Khrameeva et al., Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains. Genome Res. 30, 776–789 (2020).
64
R. D. Hodge et al., Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).
65
M. J. Kuhar, J. N. Jaworski, G. W. Hubert, K. B. Philpot, G. Dominguez, Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets. AAPS J. 7, E259–E265 (2005).
66
M. Ludwig, D. Apps, J. Menzies, J. C. Patel, M. E. Rice, Dendritic release of neurotransmitters. Compr. Physiol. 7, 235–252 (2016).
67
V. Grinevich, I. D. Neumann, Brain oxytocin: How puzzle stones from animal studies translate into psychiatry. Mol. Psychiatry 26, 265–279 (2021).
68
M. Engelmann, R. Landgraf, C. T. Wotjak, The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: An old concept revisited. Front. Neuroendocrinol. 25, 132–149 (2004).
69
H. S. Knobloch et al., Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73, 553–566 (2012).
70
Y. Yamamoto et al., Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun. Biol. 2, 76 (2019).
71
H. Mathys et al., Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).
72
J. J. Zheng et al., Oxytocin mediates early experience-dependent cross-modal plasticity in the sensory cortices. Nat. Neurosci. 17, 391–399 (2014).
73
D. Jin et al., CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41–45 (2007).
74
D. S. Quintana et al., Oxytocin pathway gene networks in the human brain. Nat. Commun. 10, 668 (2019).
75
R. Guillemin, Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11–28 (2005).
76
K. G. Mountjoy, Pro-opiomelanocortin (POMC) neurones, POMC-derived peptides, melanocortin receptors and obesity: How understanding of this system has changed over the last decade. J. Neuroendocrinol. 27, 406–418 (2015).
77
A. Abbott, How the world’s biggest brain maps could transform neuroscience. Nature 598, 22–25 (2021).
78
I. Merchenthaler, F. J. López, A. Negro-Vilar, Anatomy and physiology of central galanin-containing pathways. Prog. Neurobiol. 40, 711–769 (1993).
79
D. O’Donnell et al., “Chapter IV Localization of galanin receptor subtypes in the rat CNS” in Handbook of Chemical Neuroanatomy, R. Quirion, A. Björklund, T. Hökfelt, Eds. (Elsevier, 2002), vol. 20, 195–244.
80
L. de Lecea et al., The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A. 95, 322–327 (1998).
81
T. Sakurai et al., Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).
82
K. Fuxe et al., The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog. Neurobiol. 90, 82–100 (2010).
83
M. Uhlén et al., Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
84
E. Sjöstedt et al., An atlas of the protein-coding genes in the human, pig, and mouse brain. Science 367, eaay5947 (2020).
85
M. Uhlén et al., The human secretome. Sci. Signal. 12, eaaz0274 (2019).
86
J. Friedman, 20 years of leptin: Leptin at 20: An overview. J. Endocrinol. 223, T1–T8 (2014).
87
G. S. Sahin et al., Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons. Sci. Signal. 14, eabe4111 (2021).
88
A. Di Spiezio et al., The LepR-mediated leptin transport across brain barriers controls food reward. Mol. Metab. 8, 13–22 (2018).
89
J. Bloemer et al., Role of adiponectin in central nervous system disorders. Neural Plast. 2018, 4593530 (2018).
90
M. Beckmann, H. Johansen-Berg, M. F. Rushworth, Connectivity-based parcellation of human cingulate cortex and its relation to functional specialization. J. Neurosci. 29, 1175–1190 (2009).
91
M. D. Fox, R. L. Buckner, M. P. White, M. D. Greicius, A. Pascual-Leone, Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol. Psychiatry 72, 595–603 (2012).
92
R. F. H. Cash et al., Subgenual functional connectivity predicts antidepressant treatment response to transcranial magnetic stimulation: Independent validation and evaluation of personalization. Biol. Psychiatry 86, e5–e7 (2019).
93
E. J. Cole et al., Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am. J. Psychiatry 177, 716–726 (2020).
94
D. J. Oathes et al., Resting fMRI-guided TMS results in subcortical and brain network modulation indexed by interleaved TMS/fMRI. Exp. Brain Res. 239, 1165–1178 (2021).
95
Allen Institute for Brain Science, Allen Cell Types Database. https://portal.brain-map.org/atlases-and-data/rnaseq/human-multiple-cortical-areas-smart-seq. Accessed 1 October 2019.
96
K. E. Smith et al., Cloned human and rat galanin GALR3 receptors. Pharmacology and activation of G-protein inwardly rectifying K+ channels. J. Biol. Chem. 273, 23321–23326 (1998).
97
Z. Q. Xu, T. J. Shi, T. Hökfelt, Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on the galanin-R1 and -R2 receptors. J. Comp. Neurol. 392, 227–251 (1998).
98
X. Ma et al., Effects of galanin receptor agonists on locus coeruleus neurons. Brain Res. 919, 169–174 (2001).
99
D. Weinshenker, P. V. Holmes, Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin. Brain Res. 1641, 320–337 (2016).
100
E. Kuteeva, T. Hökfelt, T. Wardi, S. O. Ogren, Galanin, galanin receptor subtypes and depression-like behaviour. Exp. Suppl. 102, 163–181 (2010).
101
K. Mitsukawa, X. Lu, T. Bartfai, Galanin, galanin receptors, and drug targets. Exp. Suppl. 102, 7–23 (2010).
102
J. H. Krystal, C. G. Abdallah, G. Sanacora, D. S. Charney, R. S. Duman, Ketamine: A paradigm shift for depression research and treatment. Neuron 101, 774–778 (2019).
103
B. Kadriu et al., Glutamatergic neurotransmission: Pathway to developing novel rapid-acting antidepressant treatments. Int. J. Neuropsychopharmacol. 22, 119–135 (2019).
104
D. Hoyer, T. Bartfai, Neuropeptides and neuropeptide receptors: Drug targets, and peptide and non-peptide ligands: A tribute to Prof. Dieter Seebach. Chem. Biodivers. 9, 2367–2387 (2012).
105
T. Hökfelt, T. Bartfai, F. Bloom, Neuropeptides: Opportunities for drug discovery. Lancet Neurol. 2, 463–472 (2003).
106
A. P. Davenport, C. C. G. Scully, C. de Graaf, A. J. H. Brown, J. J. Maguire, Advances in therapeutic peptides targeting G protein-coupled receptors. Nat. Rev. Drug Discov. 19, 389–413 (2020).
107
M. Muttenthaler, G. F. King, D. J. Adams, P. F. Alewood, Trends in peptide drug discovery. Nat. Rev. Drug Discov. 20, 309–325 (2021).
108
R. Hargreaves et al., Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann. N. Y. Acad. Sci. 1222, 40–48 (2011).
109
P. J. Coleman, A. L. Gotter, W. J. Herring, C. J. Winrow, J. J. Renger, The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu. Rev. Pharmacol. Toxicol. 57, 509–533 (2017).
110
L. Edvinsson, P. J. Goadsby, Discovery of CGRP in relation to migraine. Cephalalgia 39, 331–332 (2019).
111
T. D. Müller et al., Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).
112
Z. Q. Zhang, C. Hölscher, GIP has neuroprotective effects in Alzheimer and Parkinson’s disease models. Peptides 125, 170184 (2020).
113
Y. Su et al., A GLP-2 analogue protects SH-SY5Y and neuro-2a cells against mitochondrial damage, autophagy impairments and apoptosis in a Parkinson model. Drug Res. (Stuttg.) 71, 43–50 (2021).
114
E. Le Mâtre, S. S. Barde, M. Palkovits, R. Diaz-Heijtz, T. G. Hökfelt, Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe. Proc. Natl. Acad. Sci. U.S.A. 110, E536–E545 (2013).
115
C. Peyron et al., Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998).
116
W. Zhong et al., “The neuropeptide landscape of human prefrontal cortex.” Figshare. https://doi.org/10.6084/m9.figshare.20442714. Deposited 5 August 2022.

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 119 | No. 33
August 16, 2022
PubMed: 35947618

Classifications

Data Availability

The transcriptomics data reported in this article for the 17 human prefrontal cortex subregions and 3 reference cortical regions (frontal, parietal, and temporal cortex), gene information, and normalized TPM values are available, open-access, and downloadable from the Human Protein Atlas database (https://www.proteinatlas.org/about/download) (53).
All data are included in the article and/or supporting information.

Submission history

Received: December 26, 2021
Accepted: June 21, 2022
Published online: August 10, 2022
Published in issue: August 16, 2022

Keywords

  1. anterior cingulate cortex
  2. in situ hybridization
  3. RNA-seq
  4. classic neurotransmitter coexistence

Acknowledgments

We thank Drs. S. Paabo (Ref. 63), E. Lein (Ref. 64) and L.H. Tsai (Ref. 71) for allowing us to use their results—they have been essential for our study. We thank Mattias Karlén for two excellent drawings (Figs. 6 and 7). We appreciate valuable advice and input from Dr. Huda Zoghbi, as well as from Drs. Rainer Landgraf, Mike Ludwig, Ming Zhao, Zhi-Qing David Xu, Tibor Harkany, and Nolan Williams. We thank Magdolna Toronyay-Kasztner for managing the HBTB database and acknowledge support from the National Genomics Infrastructure in Stockholm funded by the Science for Life Laboratory, Knut and Alice Wallenberg Foundation and the Swedish National Infrastructure for Computing (SNIC)/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. We thank the Knut and Alice Wallenberg Foundation, Swedish Research Council (2018-02753 and 2020-02956), SciLifeLab and Wallenberg Data Driven Life Science Program (Grant KAW 2020.0239), and Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002) for financial support.

Notes

Reviewers: J.D., Consejo Superior de Investigaciones Científicas and Universidad Politécnica de Madrid; I.M., University of Maryland School of Medicine; N.S., Yale University School of Medicine; and E.S., Centre for Addiction and Mental Health.

Authors

Affiliations

Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, 58225 Linköping, Sweden
Swapnali Barde1
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Nicholas Mitsios
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Csaba Adori
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Per Oksvold
Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Kalle von Feilitzen
Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Liam O’Leary
Department of Psychiatry, McGill University, Montreal, QC H3A 1A1, Canada
McGill Group for Suicide Studies, Douglas Hospital Research Centre, Montreal, QC H4H 1R3, Canada
László Csiba
Department of Neurology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
Tibor Hortobágyi
Institute of Pathology, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary
Péter Szocsics
Szentágothai János Doctoral School of Neuroscience, Semmelweis University, 1085 Budapest, Hungary
Human Brain Research Laboratory, Institute of Experimental Medicine, Eötvös Loránd Research Network (ELKH), 1052 Budapest, Hungary
Naguib Mechawar
Department of Psychiatry, McGill University, Montreal, QC H3A 1A1, Canada
McGill Group for Suicide Studies, Douglas Hospital Research Centre, Montreal, QC H4H 1R3, Canada
Zsófia Maglóczky
Human Brain Research Laboratory, Institute of Experimental Medicine, Eötvös Loránd Research Network (ELKH), 1052 Budapest, Hungary
Éva Renner
Human Brain Tissue Bank, Semmelweis University, 1085 Budapest, Hungary
Human Brain Tissue Bank, Semmelweis University, 1085 Budapest, Hungary
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Jan Mulder
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden

Notes

2
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: W.Z., M.U., J.M., and T. Hökfelt designed research; L.C., T. Hortobágyig, P.S., Z.M., E.R., and M.P. provided the postmortem brains; P.S. and Z.M. processed the postmortem brains; W.Z., S.B., N. Mitsios, and C.A. performed research; L.O. and N. Mechawar provided intellectual input and illustrations; P.O. and K.v.F. provided the infrastructure for the data; W.Z. and T. Hökfelt analyzed data; and W.Z., S.B., M.U., J.M., and T. Hökfelt wrote the paper.
1
W.Z. and S.B. contributed equally to this work.

Competing Interests

The authors declare no competing interest.

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