Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders
Abstract
:1. Introduction
1.1. CRH Synthesis
1.2. CRH Receptors
1.3. CRH Binding Protein
1.4. Synaptic CRH Activity
2. CRH Agonists and Antagonists
3. Genetically Altered Rodent Models
3.1. CRH Mutants
3.2. CRH Overexpressing (CRH-OE) Mice
3.2.1. General CRH-OE
3.2.2. Spatially Restricted CRH-OE
3.2.3. Spatially and Temporally Restricted CRH-OE
3.3. CRH-R1 and CRH-R2 Mutants
3.3.1. CRH-R1 Mutants
3.3.2. CRH-R2 Mutants
3.3.3. Combined CRH-R1 and CRH-R2 Mutants
3.3.4. Urocortin Mutants
3.4. CRH-BP Mutants
CRH Deletion Mutant | |||
---|---|---|---|
Line | Manipulation | Main Phenotypes | References |
CRH- KO | Constitutive deletion of CRH by insertion of a phosphoglycerate kinase neomycin-resistant cassette | Adrenal insufficiency | [57,58,59,60] |
↓ Stress CORT | |||
No behavioral changes | |||
CRH Overexpression (OE) Mutants | |||
Line | Manipulation | Main Phenotypes | References |
CRH-Tg | Mouse metallothionein-1 (MT-1) promoter driven CRH OE in brain, adrenal glands, heart, and testes. | Adrenal Hypertrophy | [61,66,67,70,79,80] |
Cushingoid phenotype | |||
Attentional Impairment | |||
↑ Basal CORT and ACTH | |||
↓ Locomotion | |||
↑ Anxiety in OF, EPM, LD, and black/white transition test | |||
↑ Active coping in FST | |||
↓ Despair in FST | |||
↓ Sexual receptivity in females | |||
↓ Alcohol preference | |||
Gene expression changes | |||
CRH-OE2122 | Thy-1 promoter driven CRH OE in neurons postnatally through adulthood. | Adrenal Hypertrophy | [62,65,69] |
Cushingoid phenotype at 6 months of age | |||
↑ Basal CORT | |||
Dexamethasone non-suppression | |||
↓ Acoustic startle reactivity | |||
↓ Habituation to a startle response | |||
Deficit in pre-pulse inhibition | |||
↑ Food and water consumption, and altered heart rate | |||
CRH-COEDel | Rosa26 (R26) promoter driven CRH OE in the whole body. | Cushingoid phenotype at 3-weeks of age | [64] |
↑ Adrenal weight, ↓ thymus weight | |||
↑ Basal CORT | |||
↑ Anxiety in OF, EPM, LD, and black/white transition test | |||
↓ Despair in FST | |||
CRH Overexpression (OE) Mutants | |||
Line | Manipulation | Main Phenotypes | References |
CRH-COEAPit | R26 and POMC promoter driven CRH OE in the anterior and intermediate lobes of the pituitary | Mild Cushingoid phenotype at 5-6 months of age | [64] |
↑ Basal CORT | |||
CRH-COE-Nes | R26 and Nestin promoter driven CRH OE in neurons and glia from embryonic day 10.5 | ↑ Stress-induced CORT and ACTH in male mice | [63,75,76] |
↓ Despair in FST and TST tests, reversible with CRH-R1 antagonist treatment | |||
↑ REM sleep | |||
CRH-COE-Cam | R26 and CamK2 promoter driven CRH OE in forebrain glutamatergic neurons from postnatal day 15 | Normal HPA axis activity | |
↑ REM sleep | |||
↑ Deficit in spatial performance in the MWM and Y-maze tests. | |||
CRH-COE-Dlx | R26 and Dlx promoter driven CRH OE in GABAergic interneurons from embryonic day 10.5 | Normal HPA axis activity and behavior | |
FBCRHOElife | CamK2 promoter driven forebrain CRH OE from embryonic day 0 through life | Cushingoid phenotype by 8 weeks of age | [77] |
↑ Nadir CORT and ACTH | |||
Crh-COECamCreERT2 | R26 and Camk2a-CreERT2 promoter driven CRH OE in forebrain glutamatergic neurons (OE induced by tamoxifen at postnatal week 8) | ↑ Anxiety in LD and EPM tests | [22] |
FBCRHOEdev | CamK2 promoter driven forebrain CRH OE from embryonic day 15 to postnatal day 21 | ↑Basal CORT only during CRH- OE. | [77] |
↑ Despair in FST and TST test (↓ despair in FST with antidepressants treatment) | |||
↑ Anxiety in OF, EPM, and LD tests | |||
↑ CRH-R1 mRNA in the cingulate cortex, dentate gyrus and CA1 region of the hippocampus | |||
CRF-OE | CamK2 promoter driven forebrain CRH OE from 8 to 11 weeks of age | ↑ Nadir CORT | [78] |
↓ Thymus weight in females | |||
↓ Locomotion in familiar environment | |||
↓ Despair in FST | |||
Trend towards anxiety in LD test | |||
CRH Receptor Mutants | |||
Line | Manipulation | Main Phenotypes | References |
CRH-R1-/- | Constitutive deletion (exons 5-8) of the CRH-R1 | Adrenal gland atrophy | [79,80] |
↑ PVN CRH | |||
↓ Basal CORT | |||
↓ Stress-induced CORT and ACTH in males | |||
↓ Anxiety in LD and EPM tests | |||
CRH-R1-/- | Constitutive deletion of CRH-R1 (transmembrane regions V, VI, and VII) | ↓ CRH-induced cAMP | [6,81,83,87,88] |
↓ Basal ACTH in pituitary cultures | |||
↓ Basal CORT in females | |||
↑ PVN CRH only in neonates | |||
↑ Plasma and PVN vasopressin | |||
↓ Stress-induced CORT and ACTH | |||
↓ ACTH-induced CORT | |||
↓ Anxiety in LD test basally and during alcohol withdrawal | |||
↓ Neuronal activity (cFOS) | |||
Crhr1loxP/loxPCamk2a-cre Or Cam-CRHR1 Or CRHR1Camk2aCre Or CRF1-CKO | Camk2a promoter driven deletion CRH-R1 in forebrain | ↑ Stress-induced CORT and ACTH in adults and neonates | [75,82,84,86] |
↑ CRH mRNA in PVN in adults and neonates | |||
↓ Anxiety in LD and EPM test in adults | |||
Cam-CRHR1 | |||
Hyperactive in OF test in adults | |||
↓ Neuronal activity | |||
↓ Deficit in spatial memory in Y-maze tests after chronic social defeat stress | |||
No deficit in spatial learning and memory in MWM or Y-maze tests after early life stress | |||
No chronic social defeat stress-induced deficits in the novel object recognition test | |||
No stress-induced atrophy of apical dendrites in CA3 neurons compared to control mice | |||
No stress-induced reduction of GR mRNA in CA1 and CA3 neurons compared to control mice | |||
↑ Weight gain after chronic stress | |||
No deficit in hippocampal LTP after early life stress | |||
↑ High frequency stimulation-induced LTP with early life stress | |||
Crhr1loxP/loxPNes-cre Nes-CRHR1 | Nes-Cre promoter driven deletion CRH-R1 in all neurons | ↓ Basal CORT in neonates | [85,86] |
↑ Stress-induced CORT and ACTH | |||
↓ Alcohol consumption after forced swim stress | |||
CRH Receptor Mutants | |||
Line | Manipulation | Main Phenotypes | References |
Crhr1Glu-CKO | Nex-Cre promoter driven CRH-R1 deletion in mature glutamatergic neurons | ↓ Anxiety in LD, EPM, novel object exploration, and modified hole board tests | [22] |
No effect on despair behavior in FST | |||
No effect auditory fear conditioning | |||
↑ Locomotion in LD test | |||
No effect on basal or stress-induced CORT secretion | |||
↓ Excitatory field potentials on glutamatergic neurons in the BLA | |||
↓ Facilitation of action potential firing between hippocampal DG-CA3-CA1 network | |||
Crhr1DA-CKO | Dat-CreERT2 promoter driven CRH-R1 deletion in midbrain dopaminergic neurons | ↑ Anxiety in LD, EPM, novel object exploration, and modified hole board tests | |
No effect on despair behavior in FST | |||
No effect auditory fear conditioning | |||
No effect on basal or stress-induced CORT secretion | |||
↓ Response to stress-induced DA release in PFC | |||
Crhr1GABA-CKO | DLX5/6 promoter driven CRH-R1 deletion in forebrain GABAergic neurons | No effect on anxiety behaviors | [22] |
No effect on despair behavior in FST | |||
Crhr15HT-CKO | ePet-Cre promoter driven CRH-R1 deletion in brainstem seratonergic neurons | No effect auditory fear conditioning | |
No effect on basal or stress-induced CORT secretion | |||
Crhr1CNS-CKO | Nes-Cre promoter driven CRH-R1 deletion in all neurons | No effect on anxiety behaviors | |
CRH-R2-/- | Constitutive deletion by replacing 5th-7th transmembrane domains with a neomycin-resistant cassette | ↑ Stress-induced CORT and ACTH | [90,93] |
↓ Food intake after stress of food deprivation | |||
↑Anxiety in EPM and OF tests | |||
↑ Despair in FST | |||
↑ CRH mRNA in the CeA | |||
↑ Ucn1 mRNA in Edinger-Westphal (EW) nucleus | |||
CRH-R2-/- | Constitutive deletion by replacing exons of the 3rd intracellular loop with neomycin-resistant cassette | ↑ Anxiety in EPM and LD tests in males | [91,92] |
↑ Locomotion in OF test in males | |||
↑ Stress-induced anxiety in the OF test in males | |||
↓ Neuronal activation measured by levels of phosphorylated CREB | |||
↑ Despair behavior in the FST and TST tests that is prevented when MEK/ERK pathway in the hippocampus is inhibited | |||
CRH-R2-/- | Constitutive deletion by replacing the 3rd and 4th transmembrane domains with a neomycin-resistant cassette | ↓ cAMP activity in cultured cardiomyocytes | [89] |
↑ Ucn1 mRNA in Edinger-Westphal (EW) nucleus | |||
↑ Stress-induced CORT and ACTH | |||
↓ Cardiac function with Ucn administration | |||
Altered feeding with Ucn administration | |||
CRH-R1-/-/ | CRH-R1-/- [79] were crossed to CRH-R2-/- [90] to generate these double knockout mice | ↑ PVN CRH | [7] |
CRH-R2-/- | ↓ Basal CORT and ACTH | ||
↓ HPA axis reactivity to stress | |||
CRH-R1-/-/ | CRH-R1-/-[81] were crossed to CRH-R2-/-[89] to generate these double knockout mice | ↓ Basal CORT and ACTH | [95] |
CRH-R2-/- | ↓ Anxiety in EPM and OF tests in females | ||
↑ PVN CRH and AVP | |||
Ucn mutants | |||
Line | Manipulation | Main Phenotypes | References |
Ucn-/- | Constitutive deletion of Ucn1 by replacement of the coding exon of Ucn with an EGFP-LacZ fusion reporter and a PGKneo selection cassette | Normal HPA axis activity | [97] |
No change anxiety in the EPM, OF, and LD tests | |||
Impaired acoustic startle response | |||
Ucn-/- | Constitutive deletion of Ucn1 by replacement of region encoding the mature peptide with a neomycin-resistant gene cassette | Normal HPA axis activity and feeding behavior | [98,99] |
↑ Anxiety in EPM and OF tests | |||
↓ CRH-R2 mRNA in the LS | |||
↓ Length of hair cell in organ of Corti leading to hearing impairments | |||
Ucn2 KO | Constitutive deletion of Ucn2 by insertion of a neomycin-resistant gene cassette | ↑ Nocturnal CORT and ACTH in females | [100] |
↑ AVP mRNA in the PVN and SON of females - altered drinking habits | |||
↓ Despair in the FST and TST in females | |||
No changes in anxiety in EPM and LD tests or in conditioned fear tests | |||
↑ CRH mRNA in the BnST and CeA | |||
↓ Ucn3 mRNA in the median preoptic nucleus and perifornical area | |||
↑ CRH-R2 mRNA in the BnST, LS and DR | |||
Ucn1/Ucn2 dKO | Cross breeding Ucn1 [98] and Ucn2 [100] single KOs to generate these double knockout mice. | ↑ Stress-induced plasma CORT in males | [101] |
↑ PVN CRH mRNA | |||
Hypertrophy of the zona fasciculate | |||
↓ Anxiety in EPM and OF | |||
↓ Behavioral response to acute stress in females | |||
↓ CRH-R2 mRNA in the LS | |||
↑ Amygdala CRH mRNA | |||
Ucn3tZ/tZ | Ucn3 gene was disrupted by homologous recombination and the ORF was replaced by a tau-lacZ reporter gene | Normal basal and stress-induced HPA axis responses | [102] |
No changes in anxiety-related behaviors in EPM, social interaction, and modified hole board tests compared to WT | |||
No difference in despair behavior in the FST compared to WT | |||
No genotype effect in the ASR test | |||
↑ Cocial discrimination memory | |||
Ucn tKO | Cross breeding Ucn1, 2, and 3 single KOs from [Vetter, Chen, deussing] | ↓ Basal exploration in OF 24 hours post-stress | [103] |
↑ Anxiety in OF, LD and ASR tests 24 hours after an acute stressor | |||
↑ Freezing in cued fear conditioning and ASR tests | |||
↓ Spatial learning in MWM | |||
↑ CRH-R2 mRNA in the LS and DRN | |||
↑ CRH-R1 mRNA in amygdala compared to controls 24 hours post- stress | |||
Lack of stress-induced amygdala gene modification compared to that observed in controls | |||
CRH-BP mutants | |||
Line | Manipulation | Main Phenotypes | References |
CRH-BP (transgenic) | Mouse metallothionein-1 (MT-1) promoter driven CRH-BP OE in the brain and pituitary as well as sites such as the placenta, plasma, and amniotic fluid | Normal CORT and ACTH | [104] |
↑ Weight gain (gender specific) | |||
Blunted ACTH response to LPS injection | |||
CRH-BP (transgenic) | Pituitary glycoprotein hormone a-subunit (a-GSU) promoter driven CRH-BP OE in the pituitary | Normal CORT and ACTH | [105] |
↑ PVN CRH and vasopressin | |||
↑ Locomotion | |||
Trend towards decreased anxiety in the OF | |||
CRH-BP-/- | Constitutive deletion by replacing exons1-5 with a phosphoglycerate kinase neomycin-resistant cassette | Normal CORT and ACTH | [106] |
↑ Anxiety in EPM, OF and defensive withdraw (gender specific) | |||
↓ Food intake and weight gain in males |
3.5. The Use of Viral Vectors to Modulate CRH Activity
Line (viral vector) | Manipulation | Main Phenotypes | References |
---|---|---|---|
CeA CRF OE | Long-term lentiviral CRH OE in the CeA of adult male mice. | ↓ Basal and stress-induced anxiety in OF and LD tests | [107] |
(pCSC-SP-PW-rCRF-IRES/GFP) | Behavioral testing began 4 months after lentiviral injections | ||
↓ Response to acoustic startle | |||
Habituation to startle after stress ↑ CRH-R1 mRNA in CeA | |||
CeA-CRF-OE | Short-term lentiviral CRH OE in the CeA of adult male mice when Dox is administered. | ↑ Stress-induced anxiety in LD test | [108] |
(rtTA-IRES/GFP + TRE-mCRF-IRES/RFP) | |||
Behavioral testing began 3 days after Dox administration | No effects on despair in FST or TST | ||
No effects on fear conditioning | |||
Lenti-CMV-CRF OE | Lentivirus-induced CRH OE in the CeA of female rats. | Impaired negative feedback of the HPA axis | [110] |
(LVCRFp3.CRF) | Behavioral testing began 2 weeks after lentiviral injections | ||
Disrupted reproductive and sexual function. | |||
↑ Despair in FST | |||
↑ Anxiety in acoustic startle | |||
CeA CRF OE | Lentivirus-induced CRH OE in the CeA of male rats. | ↑ CRH and vasopressin mRNA in the PVN | [109] |
LVCRFp3.CRF | Behavioral testing began 4 weeks after lentiviral injections | ||
↑Basal ACTH | |||
Dexamethasone non-suppression | |||
↑ Anxiety in EPM and defensive withdrawal tests. | |||
BnST CRF OE | Long-term lentiviral CRH OE in the BnST of male mice.Behavioral testing began 4 months after lentiviral injections | ↑ Despair in FST | [107] |
(pCSC-SP-PW-rCRF-IRES/GFP) | ↓ CRH-R1 mRNA in BnST | ||
BnST CRF OE | CRH OE in the BnST of adult male rats before or after fear conditioning in ASR tests | No changes in anxiety measures in EPM or DW tests | [111] |
(LVCRFp3.CRF) | |||
No HPA axis alterations | |||
Behavioral testing began ~2 weeks after lentiviral injections | ↓ CRH-R1 binding density in the BnST | ||
↓ CRH-R2 binding density in the DRN | |||
CRH OE induced before conditioning to fearful stimulus: | |||
No differences in baseline ASR | |||
↓ Startle sensitization and shock reactivity in ASR | |||
↓ FPS, impaired acquisition of associative fear memory | |||
CRH OE induced after conditioning to fearful stimulus: | |||
↑ FPS, enhanced fear memory expression | |||
BLA CRFR1 KD | CRH-R1 KD in the BLA of adult male mice. | ↓ Anxiety in the LD and OF tests | [112] |
(Lenti-shCRFR1) | Behavioral testing began ~2 weeks after lentiviral injections | ||
CeA CRF-KD | CRH KD in the CeA of adult male mice | ↓ Basal anxiety in the EPM test and stress-induced anxiety in LD test | [108] |
(Lenti-shCRF) | |||
Behavioral testing began ~2 weeks after lentiviral | |||
No effects on despair in FST or TST | |||
No effects on fear conditioning | |||
↑ Basal plasma CORT levels | |||
↓ Ucn3 mRNA in BnST | |||
GPe CRFR1 KD | CRH-R1 KD in the GPe of adult male mice. | ↑ Anxiety in the LD, OF and EPM tests | [113] |
(Lenti-shCRFR1) | Behavioral testing began ~2 weeks after lentiviral injection | ||
No changes in locomotion | |||
↓ Enkephalin protein in GPe, possible mechanism for increased anxiety | |||
rPFA-Ucn3 OE | Transgenic mice with Ucn3 under the control of a TRE were injected in the rPFA with lentivirus containing rtTA. Ucn3 OE occurs when Dox is administered | ↑ Anxiety in the LD and OF tests | [114] |
(Lenti-rtTA) | ↑ Metabolic rate, but has no effect on food intake | ||
↓ Insulin sensitivity |
4. Human Gene Polymorphisms
4.1. CRH
4.2. CRHR1
4.3. CRHR2
4.4. CRHBP
4.5. The Potential of CRH-Pathways Genetic Studies
GENE | Polymorphism | Associated Disorder | Effect | References |
---|---|---|---|---|
CRH | 173 bp in the dinucleotide repeat marker CRH-PCR1 | Behavioral inhibition | Risk promoting | [115,116] |
rs6999100 (CC) | ||||
rs6159 (GG) | ||||
rs1870393 (CC) | ||||
CRHR1 | rs7209436 (TT) rs110402 ((AA) rs242924 (TT) | Depression with adverse early life experiences | Protective | [117,118,119,120,121] |
T-A-T haplotype | ||||
CRHR1 | T-A-T haplotype rs17689882 | Depression with childhood physical neglect | Risk promoting | [122] |
rs16940674 | ||||
rs16940665 | ||||
CRHR1 | rs110402 (TT) | Depression onset and seasonal episodes | Risk promoting | [125] |
CRHR1 | rs110402 (GG) | Depression vulnerability | Risk promoting | [16] |
CRHR1 | G-G-T haplotype | Genetic susceptibility to major depression and response to antidepressant treatment | Risk promoting | [126,127,128] |
rs1876828 (GG) | ||||
rs242939 (GG) | ||||
rs242941 (TT) | ||||
CRHR1 | rs1876831 (CC) | Alcohol consumption with life stress | Risk promoting | [72,129,130] |
rs242938 (A) | ||||
CRHR1 | rs4792887 (TT) | Suicidality after low stress exposure | Risk promoting | [135] |
CRHR2 | rs2270007 (GG) | Decreased response to antidepressant treatment in depressed patients | Risk promoting | [125] |
CRHR2 | 5-2-3 haplotype (allele 3 in GT) | Suicidal behavior in bipolar disorder | Risk promoting | [136] |
CRHBP | rs10473984 (TT) | Remission and decreased depressive symptoms with citalopram treatment | Risk promoting | [35] |
CRHBP | rs1875999 (TT) | Unipolar depression | Risk promoting | [137] |
CRHBP | rs10055255 (TT) | Stress-induced alcohol craving and negative mood | Risk promoting | [138] |
CRHBP CRHR1 | rs3811939 (GG) | Comorbid alcoholism in Schizophrenic patients | Risk promoting | [134] |
rs110402 (TT) | ||||
CRHBP CRHR1 | rs1875999 | Suicidal behavior in Schizophrenia | Risk promoting | [139] |
rs169400665 |
5. Targeting the CRH Pathway for Therapy
6. Conclusions
Acknowledgments
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Laryea, G.; Arnett, M.G.; Muglia, L.J. Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders. Behav. Sci. 2012, 2, 135-171. https://doi.org/10.3390/bs2020135
Laryea G, Arnett MG, Muglia LJ. Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders. Behavioral Sciences. 2012; 2(2):135-171. https://doi.org/10.3390/bs2020135
Chicago/Turabian StyleLaryea, Gloria, Melinda G. Arnett, and Louis J. Muglia. 2012. "Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders" Behavioral Sciences 2, no. 2: 135-171. https://doi.org/10.3390/bs2020135