Carrive Research Lab - Brain, Blood Pressure and Stress

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Research

Aim and Concepts
The aim of the research conducted in my laboratory is to understand how the brain controls the autonomic and cardiovascular changes associated with stress and emotions.

We are particularly interested in conditioned fear responses. Conditioned fear responses are conditioned emotional responses that occur in anticipation of unpleasant confrontations or events. We have all experienced, for example, the sweaty hands and pounding heart that occur as we are waiting for the mail and bad news is expected or when we face an important meeting for which we are not well prepared. These fear responses are generated in the brain and mediated by a neural network that spans the entire neuraxis, from the forebrain where past experiences are recalled, down to the lower brainstem and spinal cord where autonomic preganglionic neurons are located. We are exploring this network and trying to understand how it is organized, functionally and anatomically.

The outcomes of this research will lead to a better understanding of:

1. The neural substrate of emotions and stress responses,
2. The central regulation of cardiovascular function,
3. The functional/anatomical organization of the limbic forebrain and reticular formation.



Methods
Experiments are conducted in conscious freely moving rats. We use a simple model of conditioned fear called conditioned fear to context. This form of conditioned fear is evoked by re-exposure to a chamber in which small electric footshocks have previously been administered on a few occasions). The fear of receiving more shocks in the box is characterized by a freezing immobility and ultrasonic vocalizations (22 KHz). We have found that it is also associated with a marked and sustained increase in mean arterial blood pressure (+30 mmHg). Our research is about this cardiovascular response and its neural substrate.

• The approach is multi-disciplinary and at the crossroad of animal behavior, cardiovascular physiology and neuroanatomy. Some of the techniques used are:
• Recording of blood pressure, body temperature and activity by radio-telemetry, a new technology that allows continuous recording in conscious, freely moving rats (for more information see http://www.datasci.com).
• Recording of cutaneous temperature using digital infrared thermography.
• Immunohistological detection of Fos, the protein product of the immediate early gene c-fos. Fos is a commonly used marker of neuronal activity. Here it is used to identify the brain regions that are activated during conditioned fear.
• Neuronal tract tracing (retrograde and anterograde) in combination with Fos, to identify the connections between brain regions activated by conditioned fear.
• Intracerebral microinjections of neuronal blockers (e.g., GABA agonists or glutamate antagonists), to verify physiologically the role of brain regions in the cardiovascular response to conditioned fear.

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Staff

Dr Daniel ML Vianna (Postdoctoral Fellow)
Angela Laird (PhD candidate, co-supervision with Prof Phil Waite)
Leanne Luong (Honours student)
Nick Olsen (Honours student)
Andrew Marks (ILP student)

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Research Grants

Present

• 2008-2010 NHMRC Research Grant. Central blockade of sympathetic responses to emotional stressors. P.Carrive

Past

• 2006-2007 NHF Research Grant. Role of Medullary Raphe Nuclei in the cardiovascular response to psychological stress. P. Carrive
• 2006 UNSW Goldstar award. Role of Medullary Raphe Nuclei in the cardiovascular response to psychological stress. P. Carrive
• 2006-2008. International Spinal Research Trust. Improving cardiovascular function after spinal cord injury. P. Waite, P. Carrive and A. Mackay-Sim
• 2004-2006 NSW Department of Health. Repair of the injured spinal cord: trialling potential cell therapies. P. Waite, S. Rutkowski, D. Ma, A. Mackay-Sim, B. Tuch, P Carrive, D Tracey, E Burcher, K Ashwell, B Lee, P Siddall, H Alexander, D Brazier, R Millard, H Tao, D Vu.
• 2004 - 2006 NHRMC Project Grant. How the brain suppresses bad memories. F Westbrook, P Carrive, R Richardson.
• 2004 NHRMC Equipment Grant. Infrared thermographic camera. P Carrive, V Macefield, P Waite, T Carroll and S Boutcher.
• 2003-2004 NHF Research Grant. Role of hypothalamic orexin in the cardiovascular response to psychological stress. P Carrive
• 2003 Goldstar Award UNSW. How the brain controls blood pressure during psychological stress: orexin vs noradrenaline. P Carrive.
• 2000-2002 NHMRC Research Grant. Premotor sympathetic control of blood pressure during psychological stress: hypothalamus versus medulla. P Carrive
• 1997 - 1999 NHMRC Research Grant. Suprameduallry control of medullary autonomic centers during conditioned stress. P Carrive.

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Publications (from 1999 - present)

Books

Paxinos G., Carrive P, Wang, HQ and Wang PY (1999) A Chemoarchitectonic Atlas of the Rat Brainstem. Academic Press, San Diego. See the cover at Academic Press or Amazon.com.

Chapters in books

Carrive, P. and Morgan MM (2004). The periaqueductal gray. In: G Paxinos (Ed) The human nervous system (2nd edition), Academic Press, San Diego

Carrive, P. (2007) Aversive Emotions: Emotional Control of the Autonomic Nervous System. In: L. Squire, T. Albright, F. Bloom, F. Gage and N. Spitzer New Encyclopedia of Neuroscience, Elsevier (in press)

Carrive, P. (2007) Central circulatory control: psychological stress (and the defence reaction) and In: I.Llewellyn-Smith and A.Verberne (Eds) Central Regulation of Autonomic Function 2nd Edition. Oxford University Press (in press)

Journal Articles

Carrive P, Lee, J and Su, A. (1999) Lidocaine blockade of amygdala output in fear conditioned rats reduces Fos expression in the ventrolateral periaqueductal gray. Neuroscience, 95: 1071-1080.

Carrive P (2000) Conditioned fear to environmental context: cardiovascular and behavioral components in the rat. Brain Res, 858: 440-445.

Morgan MM and Carrive P (2001) Activation of the Ventrolateral PAG Reduces Locomotion but not Mean Arterial Pressure in Awake, Freely Moving Rats. Neuroscience 102: 905-910.

Dielenberg, RA , Carrive, P and McGregor, IS (2001) The cardiovascular and behavioral response to cat odor in rats: unconditioned and conditioned effects. Brain Research 897: 228-237.

Carrive, P (2002) Cardiovascular and behavioral components of conditioned fear to context after ganglionic and alpha-adrenergic blockade. Autonomic Neuroscience 98:90-93.

Walker P and Carrive P (2003) Role of ventrolateral periaqueductal gray neurons in the behavioural and cardiovascular responses to contextual conditioned fear and post-stress recovery. Neuroscience 116: 897-912

Leman, S, Dielenberg RA and Carrive, P (2003) Effect of dorsal priaqueductal gray lesion on cardiovascular and behavioural responses to contextual conditioned fear in rats. Behavioural Brain Research 143: 169-176

Dielenberg RA, Leman, S and Carrive, P (2004) Effect of dorsal priaqueductal gray lesion on cardiovascular and behavioural responses to cat odour exposure in rats. Behavioural Brain Research 153: 487–496

Choi, EA, Leman, S, Vianna D, Waite, PM and Carrive, P (2005) . Expression of cardiovascular and behavioural components of conditioned fear to context in T4 spinally transected rats. Autonomic neuroscience 120: 26-34

Vianna, DML and Carrive, P (2005). Changes in cutaneous and body temperature during and after conditioned fear to context in the rat. European Journal of neuroscience 21: 2505-2512

McNally G. and Carrive, P. (2006). A telemetric examination of cardiovascular function during the development of and recovery from opiate dependence. Physiology & Behavior 88(1-2):55-60

Carrive, P. (2006). Dual activation of cardiac sympathetic and parasympathetic components during conditioned fear to context in the rat. Clinical and Experimental Pharmacology and Physiology 33:1260-1263.

Florenzano, F., Viscomi, M.T., Mercaldo, V., Longone, P., Bernardi, G., Bagni, C., Molionari, M. and Carrive, P. (2006). P2X2R purinergic receptor subunit mRNA and protein are expressed by all hypothalamic hypocretin/orexin neurons. Journal of Comparative Neurology 498(1): 58-67.

Laird A, Carrive P. and Waite P (2006). Cardiovascular and temperature changes in spinal cord injured rats at rest and during autonomic dysreflexia, J Physiol (Lond) 577, 539-548.

Furlong Y. and Carrive P. (2007). Neurotoxic lesions centered on the perifornical hypothalamus abolish the cardiovascular and behavioural responses of conditioned fear to context but not restraint. Brain Research 1128, 107-109.

Florenzano F, Carrive P, Viscomi M.T., Ferrari F., Latini L., Conversi D., Cabib S., Bagni C. and Molinari M. (2007) Cortical and subcortical distribution of P2X[1]R immunoreative neurons in the rat forebrain. Neuroscience (in press)

Laird A., Finch A.M., Waite P.M.E. and Carrive P. (2007) Peripheral changes above and below injury level lead to exaggerated vascular responses following high spinal cord injury. American Journal of Physiology (in press).

Some conference abstracts (1999 -present)

Carrive P, Bowen R and Walker P, (1999) Role of the perifornical and paraventricular nuclei in the cardiovascular component of conditioned stress demonstrated by bilateral blockade with kynurenic acid and and muscimol. ANS meeting, Hobart, 1999. Proc. Aust. Neuroscience Soc. 10: 76

Walker P and Carrive P (2000) Muscimol blockade of the ventrolateral periaqueductal gray reduces the freezing immobility but not the hypertensive response of conditioned fear. Proc. Aust. Neuroscience Soc. 11: 252

Carrive P and Fontes W (2000) The hypertensive response of conditioned fear almost doubles after sinoaortic barodenervation. Proc. Aust. Neuroscience Soc. 11: 13

Carrive P (2001) Sinoaortic barodenervation only marginally increase Fos expression in the RVLM of fear conditioned rats. Proc. Aust. Neuroscience Soc. 12: 45

Dielenberg RA, Carrive P and McGregor I (2001) The cardiovascular and behavioural response to cat odour in rats: conditioned and unconditioned effects. Proc. Aust. Neuroscience Soc. 12: 45

Carrive P and Walker P (2001) Effects of chemical blockade of the ventrolateral periaqueductal gray on conditioned fear and recovery after fear: cardiovascular and behavioral components. American Neuroscience Society meeting, San Diego, Cal. Soc. Neurosci. Abstr. 27: 651

Carrive P (2002) Role of the medial hypothalamus and ventrolateral PAG in the cardiovascular response to psychological stress and its recovery. Proc. Aust. Neuroscience Soc. 13: 118

Carrive P, Leman S, Dielenberg R and Walker P (2002) Role of the ventrolateral periaqueductal gray in the expression and recovery of conditioned fear. Proc. Aust. Neuroscience Soc. 13: 17

Leman S and Carrive P (2002) Which limbic forebrain structure(s) activate the perifornical hypothalamus during conditioned fear ? Proc. Aust. Neuroscience Soc. 13: 100

Carrive P, Walker P, Leman S and Dielenberg R (2002) The dorsal hypothalamus mediates the pressor response of contextual fear while the ventrolateral periaqueductal gray mediates the depressor response of recovery after fear. FENS Abstr. 1: A025.2

Carrive P and Lee JSH (2003) Activation of hypothalamic hypocretin neurons by conditioned fear American neuroscience Society meeting New Orleans. Soc Neurosci. Abstr. 81.12

Lee JSH and Carrive, P (2003) Conditioned fear to context increases Fos expression in hypothalamic orexin neurons Proc. Aust. Neuroscience Soc. 14: Oral 01-01

Leman S and Carrive P (2003) Role of the bed nucleus of the stria terminalis and preoptic area in the cardiovascular response of contextual conditioned fear in rats. Proc. Aust. Neuroscience Soc. 14: Pos 207

Choi, EA, Leman, S, Waite, PME and Carrive, P (2003) . Expression of cardiovascular and behavioural components of conditioned fear to context in Chronic paraplegic rats. Proc. Aust. Neuroscience Soc. 14: Pos 208

Furlong, TM and Carrive P (2004) The perifornical region of the hypothalamus is involved in the cardiovascular response of conditioned fear but not restraint stress Proc. Aust. Neuroscience Soc. 15: 265

Carrive, P and Leman, S (2004) SB-334867-A, an antagonist of the hypocretin receptor 1 (HcrtR1) has no effect on the cardiovascular and behavioural response to conditioned fear. Proc. Aust. Neuroscience Soc. 15, 292

Laird, AS, Waite, PME and Carrive, P (2004) A strain difference in the pressor response of chronic spinal cord injured rats to intravenous injection of phenylephrine. Proc. Aust. Neuroscience Soc. 15, 247

Dampney R.A.L., Sheriff, M.J., Horiuchi, J. Killinger S. and Carrive P. (2005) Effect of chronic Angiotensin II infusion on the cardiovascular responses to disinhibition of the paraventricular nuclei. Proc. Aust. Neuroscience Soc. 16, 22

Vianna D.M.L. and Carrive P. (2005) Retrograde lesions of spinally projecting A5 neurons have no effect on the expression of the cardiovascular and behavioral components of conditioned fear. Proc. Aust. Neuroscience Soc. 16, 21

Vianna D.M.L. and Carrive P. (2005) Changes in skin temperature revealed by infrared thermography during and after conditioned fear to context in the rat. Proc. Aust. Neuroscience Soc. 16, 45

Furlong T.M. and Carrive P. (2005) Hypocretin/orexin neurons are more active during contextual fear than during restraint stress. Proc. Aust. Neuroscience Soc. 16, 114

Laird, A.S., Waite, P.M.E and Carrive, P (2005) Widespread vascular hyper-reactivity to noradrenaline in spinal cord injured rats. Proc. Aust. Neuroscience Soc. 16, 108

Carrive, P (2005) A central network controlling cardiovascular changes during psychological stress . Autonom. Neurosci. 119, 103

Furlong T.M. and Carrive P. (2005) Hypocretin/orexin neurons and the perifornical hypothalamus play a more important role in contextual fear than in restraint stress. Soc. Neurosci. Abstr. 304.11

Laird A.S., Carrive P. and Waite P.M.E. (2006) Cardiovascular and temperature changes in spinal cord injured rats at rest and during autonomic dysreflexia Neuroscience Meeting Planner, on line 586.7

F. Florenzano, M. T. Viscomi, V. Mercaldo, P. Longone, G. Bernardi, P. Carrive, C. Bagni and M. Molinari (2006) P2X2R subunit mRNA and protein are expressed by hypothalamic hypocretin/orexin neurons. Neuroscience Meeting Planner, on line 790.4

Vianna, D.M.L, Allen C. and Carrive P. (2007) Changes in autonomic and behavioural responses to fear after medullary raphe inactivation. IBRO 2007 POS-FRI 168

Marks A., Vianna D.M.L. and Carrive P. (2007) Brown fat activation during psychological stress in the rat. An infrared thermographic study. IBRO 2007 POS-SUN-323

Laird A.S., Waite P.M.E. and Carrive P. (2007) Chronic spinal cord injury results in vascular hyperresponsiveness both above and below the level of injury. IBRO 2007. POS-FRI-175

Kalinčík T., Mackay-Sim A., Carrive P. and Waite P M.E. (2007) Transplants of olfactory ensheathing cells promote recovery of cardiovascular functions after autonomic dysreflexia in rats with high spinal cord injury. IBRO 2007 POS-MON-85

Laird A., Carrive P. and Waite P. (2007) Treadmill training after SCI leads to spinal morphological changes and accelerated development of autonomic dysreflexia. ISAN 2007 Autonom. Neurosci. p 56.

Carrive P., Marks A. and Vianna D.M.L. (2007) What causes conditioned fear-induced hyperthermia in the rat? An infrared thermographic study. ISAN 2007 Autonom. Neurosci. p 65.

Vianna D.M.L., Allen A. and Carrive P. (2007) Pharmacological dissociation of autonomic and behavioural responses to fear in the medullary raphe. ISAN 2007 Autonom. Neurosci. p 131.