The Neonatal Ventral Hippocampal Lesion (NVHL) Rodent Model of Schizophrenia

Anne Marie Brady1

1 Department of Psychology and Neuroscience Program, St. Mary's College of Maryland, St. Mary's City, Maryland
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.55
DOI:  10.1002/cpns.15
Online Posting Date:  October, 2016
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Animal models are crucial to the study of the neurobiological bases of psychiatric disorders, but schizophrenia is a particularly challenging disorder to model given the complexity and heavily verbal nature of its symptoms. This unit describes a developmental surgical rodent model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. This widely used model produces reliable behavioral abnormalities that are comparable to those observed in patients, as well as anatomical and neurophysiological disruptions in forebrain areas that are also implicated in schizophrenia. A brief background of the development and validity of the NVHL model is discussed here, along with detailed procedures for producing the model in rats. Critical issues particular to neonatal surgery are discussed, and representative histological and behavioral results are presented. © 2016 by John Wiley & Sons, Inc.

Keywords: developmental; hippocampus; prefrontal cortex; rodent model; schizophrenia

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Table of Contents

  • Introduction
  • Basic Protocol 1: Presurgical Preparation of Animals
  • Basic Protocol 2: The NVHL Surgical Procedure
  • Support Protocol 1: Preparation of the Stereotaxic Frame and Injection Cannula
  • Reagents and Solutions
  • Commentary
  • Literature Cited
  • Figures
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Basic Protocol 1: Presurgical Preparation of Animals

  • Pregnant Sprague Dawley rats
  • Rodent housing facility
  • Scale, to weigh pups
  • Additional reagents and equipment for euthanasia ( appendix 4H)

Basic Protocol 2: The NVHL Surgical Procedure

  • Rat dams and litters (PD 7 ± 1)
  • Artificial cerebrospinal fluid (aCSF; see recipe)
  • 10 µg/µl ibotenic acid (see recipe)
  • Scale, to weigh pups
  • Polyethylene (PE‐20) tubing (i.d. 0.38 to 0.4 mm, o.d. 1.09 to 1.1 mm)
  • Injection cannula assembly (26‐G needle with sharp bevel [e.g., Hamilton 775802] and depth marker [see protocol 3Support Protocol])
  • 1‐ml syringes with 23‐G or 25‐G needles
  • 10‐μl infusion syringe (e.g., Hamilton 80300)
  • Syringe infusion pump capable of delivering 15 nl/min
  • Crushed ice and ice bucket
  • Stereotaxic frame, modified (see protocol 3Support Protocol)
  • Self‐adhesive label tape
  • Scalpel blades
  • Ear punch or tattooing equipment
  • Clip applier and clips (e.g., Autoclip System) or wound closure glue
  • Toothed iris tissue forceps (1 × 2 teeth, straight, 4 in.)
  • Rubber pipet bulbs
  • Warming pads (e.g., Deltaphase 8 in. × 8 in. pads)
  • Alcohol (for sterilizing instruments) or heat‐based instrument sterilizer (e.g., Germinator 500)

Support Protocol 1: Preparation of the Stereotaxic Frame and Injection Cannula

  • Section of thick Styrofoam or similar material, sized to fit inside the stereotaxic frame
  • Small animal stereotaxic frame with ear bars (e.g., Kopf Model 900)
  • Standard vertical electrode holder with clamp (e.g., Kopf Model 1770)
  • Circular (bulls‐eye) level (allows leveling in two dimensions)
  • Polyethylene (PE‐20) tubing (i.d. 0.38 to 0.4 mm, o.d. 1.09 to 1.1 mm)
  • Injection cannula (26‐G needle with sharp bevel [e.g., Hamilton 775802])
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Literature Cited

Literature Cited
  Berg, S.A., Sentir, A.M., Cooley, B.S., Engleman, E.A., and Chambers, R.A. 2014. Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions. Addict. Biol. 19:1020‐1031. doi: 10.1111/adb.12082.
  Brady, A.M., Saul, R.D., and Wiest, M.K. 2010. Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia. Neuropharmacology 59:605‐611. doi: 10.1016/j.neuropharm.2010.08.012.
  Brady, A.M., McCallum, S.E., Glick, S.D., and O'Donnell, P. 2008. Enhanced methamphetamine self‐administration in a neurodevelopmental rat model of schizophrenia. Psychopharmacology 200:205‐215. doi: 10.1007/s00213‐008‐1195‐7.
  Chambers, R.A. and Self, D.W. 2002. Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: An animal model of dual diagnosis schizophrenia. Neuropsychopharmacology 27:889‐905. doi: 10.1016/S0893‐133X(02)00365‐2.
  Chambers, R.A., Krystal, J.H., and Self, D.W. 2001. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol. Psychiatry 50:71‐83. doi: 10.1016/S0006‐3223(01)01134‐9.
  Chambers, R.A. and Lipska, B.K. 2011. A method to the madness: Producing the neonatal ventral hippocampal lesion rat model of schizophrenia. In Animal Models of Schizophrenia and Related Disorders, Neuromethods, vol. 59 (P. O'Donnell, ed.) pp. 1‐24. Humana Press, New York.
  Chambers, R.A., Moore, J., McEvoy, J.P., and Levin, E.D. 1996. Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology 15:587‐594. doi: 10.1016/S0893‐133X(96)00132‐7.
  Danneman, P.J. and Mandrell, T.D. 1997. Evaluation of five agents/methods for anesthesia of neonatal rats. Lab. Anim. Sci. 47:386‐395.
  Gruber, A.J., Calhoon, G.G., Shusterman, I., Schoenbaum, G., Roesch, M.R., and O'Donnell, P. 2010. More is less: A disinhibited prefrontal cortex impairs cognitive flexibility. J. Neurosci. 30:17102‐17110. doi: 10.1523/JNEUROSCI.4623‐10.2010.
  Karlsson, R.M., Kircher, D.M., Shaham, Y., and O'Donnell, P. 2013. Exaggerated cue‐induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia. Psychopharmacology 226:45‐51. doi: 10.1007/s00213‐012‐2882‐y.
  Lewis, D.A. and Levitt, P. 2002. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25:409‐432. doi: 10.1146/annurev.neuro.25.112701.142754.
  Lipska, B.K. and Weinberger, D.R. 1994. Subchronic treatment with haloperidol and clozapine in rats with neonatal excitotoxic hippocampal damage. Neuropsychopharmacology 10:199‐205. doi: 10.1038/npp.1994.22.
  Lipska, B.K. and Weinberger, D.R. 2000. To model a psychiatric disorder in animals: Schizophrenia as a reality test. Neuropsychopharmacology 23:223‐239. doi: 10.1016/S0893‐133X(00)00137‐8.
  Lipska, B.K., Jaskiw, G.E., and Weinberger, D.R. 1993. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia. Neuropsychopharmacology 9:67‐75. doi: 10.1038/npp.1993.44.
  Lipska, B.K., Aultman, J.M., Verma, A., Weinberger, D.R., and Moghaddam, B. 2002. Neonatal damage of the ventral hippocampus impairs working memory in the rat. Neuropsychopharmacology 27:47‐54. doi: 10.1016/S0893‐133X(02)00282‐8.
  Lipska, B.K., Swerdlow, N.R., Geyer, M.A., Jaskiw, G.E., Braff, D.L., and Weinberger, D.R. 1995. Neonatal excitotoxic hippocampal damage in rats causes post‐pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology 122:35‐43. doi: 10.1007/BF02246439.
  Lodge, D.J. 2013. The MAM rodent model of schizophrenia. Curr. Protoc. Neurosci. 63:9.43.1‐9.43.7. doi: 10.1002/0471142301.ns0943s63.
  Marquis, J.P., Goulet, S., and Dore, F.Y. 2008. Neonatal ventral hippocampus lesions disrupt extra‐dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats. Neurobiol. Learn. Mem. 90:339‐346. doi: 10.1016/j.nlm.2008.04.005.
  O'Donnell, P. 2012. Cortical disinhibition in the neonatal ventral hippocampal lesion model of schizophrenia: New vistas on possible therapeutic approaches. Pharmacol. Ther. 133:19‐25. doi: 10.1016/j.pharmthera.2011.07.005.
  Palacorolla, H.L., Gyawali, U., Jarrin, S.E., Smith, N.K., and Brady, A.M. 2013. Compulsive cocaine‐seeking in the neonatal ventral hippocampal lesion model of schizophrenia. 2013 Neuroscience Meeting Planner Program no. 151:103. San Diego: Society for Neuroscience.
  Paxinos, G. and Watson, C. 1988. The Rat Brain in Stereotaxic Coordinates, 4th ed. Academic Press, San Diego.
  Pelloux, Y., Everitt, B.J., and Dickinson, A. 2007. Compulsive drug seeking by rats under punishment: Effects of drug taking history. Psychopharmacology 194:127‐137. doi: 10.1007/s00213‐007‐0805‐0.
  Placek, K., Dippel, W.C., Jones, S., and Brady, A.M. 2013. Impairments in set‐shifting but not reversal learning in the neonatal ventral hippocampal lesion model of schizophrenia: Further evidence for medial prefrontal deficits. Behav. Brain Res. 256C:405‐413. doi: 10.1016/j.bbr.2013.08.034.
  Sams‐Dodd, F., Lipska, B.K., and Weinberger, D.R. 1997. Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology 132:303‐310. doi: 10.1007/s002130050349.
  Swerdlow, N.R., Braff, D.L., Taaid, N., and Geyer, M.A. 1994. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch. Gen. Psychiatry. 51:139‐154. doi: 10.1001/archpsyc.1994.03950020063007.
  Tseng, K.Y., Chambers, R.A., and Lipska, B.K. 2009. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav. Brain Res. 204:295‐305. doi: 10.1016/j.bbr.2008.11.039.
  van Os, J. and Kapur, S. 2009. Schizophrenia. Lancet 374:635‐645. doi: 10.1016/S0140‐6736(09)60995‐8.
  Weinberger, D.R. 1999. Cell biology of the hippocampal formation in schizophrenia. Biol. Psychiatry 45:395‐402. doi: 10.1016/S0006‐3223(98)00331‐X.
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