Differential rewarding effects of electrical stimulation of the lateral hypothalamus and parabrachial complex: Functional characterization and the relevance of opioid systems and dopamine

Background: Since the discovery of rewarding intracranial self-stimulation by Olds and Milner, extensive data have been published on the biological basis of reward. Although participation of the mesolimbic dopaminergic system is well documented, its precise role has not been fully elucidated, and some authors have proposed the involvement of other neural systems in processing specific aspects of reinforced behaviour. Aims and methods: We reviewed published data, including our own findings, on the rewarding effects induced by electrical stimulation of the lateral hypothalamus (LH) and of the external lateral parabrachial area (LPBe) – a brainstem region involved in processing the rewarding properties of natural and artificial substances – and compared its functional characteristics as observed in operant and non-operant behavioural procedures. Results: Brain circuits involved in the induction of preferences for stimuli associated with electrical stimulation of the LBPe appear to functionally and neurochemically differ from those activated by electrical stimulation of the LH. Interpretation: We discuss the possible involvement of the LPBe in processing emotional-affective aspects of the brain reward system.Desde el descubrimento de la estimulación eléctrica reforzante, por parte de Olds y Milner, se han publicado muchas investigaciones sobre las bases biológicas del refuerzo. Aunque la participación del Sistema Dopaminérgico Mesolímbico está bien documentada, su papel concreto no ha sido plenamente dilucidado y algunos investigadores han propuesto la implicación de otros sistemas neurales en el procesamiento de aspectos específicos de la conducta reforzante. Objetivo y método: Revisamoos los datos publicados -incluyendo nuestros resultados- sobre los efectos reforzantes de la estimulación eléctrica del hipotálamo lateral y del área parabraquial lateral externa (LPBe) -una región troncoencefálica involucrada en el procesamiento de las propiedades reforzantes de sustancias naturales y artificiales- y comparamos sus caracteristicas funcionales en procedimientos de aprendizaje operantes y no operantes. Resultado: Los circuitos cerebrales involucrados en la inducción de preferencias por los estímulos con que es asociada la estimulación eléctrica del LPBe parecen diferir funcional y neuroquímicamente de los activados por estimulación eléctrica del hipotálamo lateral. Interpretación: Discutimos la posible participación del LPBe en el procesamiento de los aspectos afectivo-emocionales del circuito de recompensa cerebra

DETECTING BRAIN-WIDE INTRINSIC CONNECTIVITY NETWORKS USING fMRI IN MICE

Functional neuroimaging methods in mice are essential for unraveling complex neuronal networks that underlie maladaptive behavior in neurological disorder models. By using fMRI to detect intrinsic connectivity networks in mice, we can examine large scale alteration in brain activity and functional connectivity to establish causal associations in brain network changes. The work presented in this dissertation is organized into five chapters. Chapter 1 provides the necessary background required to understand how functional neuroimaging tools such as fMRI detect signal changes attributed to spontaneous neuronal activity of intrinsic connectivity networks in mice. Chapter 2 describes the development of our isotropic fMRI acquisition sequence in mice and semi-automated pipeline for mouse fMRI data. Naïve mouse fMRI scans were used to validated the pipeline by reliably and reproducibly extracting intrinsic connectivity networks. Chapter 3 establishes the development and validation of a novel superparamagenetic iron-oxide nanoparticle to enhance fMRI signal sensitivity. Chapter 4 studies the effects norepinephrine released by locus coeruleus neurons on the default mode network in mice. Norepinephrine release selectively enhanced neuronal activity and connectivity in the Frontal module of the default mode network by suppressing information flow from the Retrosplenial-Hippocampal to the Association modules. Chapter 5 addresses the implications of our findings and addresses the limitations and future studies that can be conducted to expand on this research.Doctor of Philosoph

Neuro-behavioural impact of changes in hippocampal neural activity

Hippocampal metabolic hyperactivity and neural disinhibition, i.e. reduced GABAergic inhibition, have been associated with schizophrenia, although a causal link between disinhibition and metabolic hyperactivity remains to be demonstrated. Regional neural disinhibition might also disrupt neural activation in projection sites, such as the prefrontal cortex and striatum, which may contribute to cognitive impairments and positive symptoms characteristic of schizophrenia. To further examine the brain-wide impact of hippocampal disinhibition and the associated behavioural and cognitive changes, we combined ventral hippocampal infusion of the GABA-A antagonist picrotoxin with translational neural imaging and behavioural methods in rats. First, we used a conditioned emotional response paradigm to assess the impact of hippocampal disinhibition on aversive conditioning and salience modulation in the form of latent inhibition (chapter 2), both of which have been reported to be disrupted in schizophrenia. These experiments demonstrated hippocampal disinhibition caused disrupted cue and contextual fear conditioning, whilst we found no evidence that hippocampal disinhibition affects salience modulation as reflected by latent inhibition of fear conditioning. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing at hippocampal projection sites. Second, we used SPECT imaging to map changes in brain-wide activation patterns caused by hippocampal GABA dysfunction (chapter 3). SPECT experiments revealed increased neural activation around the infusion site in the ventral hippocampus, resembling metabolic hippocampal hyperactivity consistently reported in schizophrenia. In contrast, activation in the dorsal hippocampus was significantly reduced. This resembles the finding of anterior hippocampal hyperactivity coupled with reduced posterior hippocampal activation in patients with schizophrenia. Hippocampal disinhibition also caused marked extra-hippocampal activation changes in neocortical and subcortical sites, including sites implicated in fear learning and anxiety such as the medial prefrontal cortex (mPFC), septum, lateral hypothalamus and extended amygdala which may contribute to the disruption of fear conditioning demonstrated in chapter 2. Importantly, increased activation in the mPFC corresponds with previously reported prefrontal-dependent attentional deficits caused by hippocampal disinhibition. Third, to complement these findings we used magnetic resonance spectroscopy (MRS) to determine the effects of hippocampal disinhibition on neuro-metabolites within the mPFC (chapter 4). Using MRS, we demonstrated that hippocampal disinhibition causes metabolic changes in the mPFC, reflected by increased myo-inositol and reduced GABA concentrations. Overall, our results demonstrate ventral hippocampal disinhibition causes regional metabolic hyperactivity, supporting a causal role between GABA dysfunction and increased anterior hippocampal activity. In addition, hippocampal disinhibition causes activation and metabolic changes at distal sites, which may contribute to clinically relevant behavioural deficits, including impaired aversive conditioning, as demonstrated in our behavioural studies

Neuro-behavioural impact of changes in hippocampal neural activity

Hippocampal metabolic hyperactivity and neural disinhibition, i.e. reduced GABAergic inhibition, have been associated with schizophrenia, although a causal link between disinhibition and metabolic hyperactivity remains to be demonstrated. Regional neural disinhibition might also disrupt neural activation in projection sites, such as the prefrontal cortex and striatum, which may contribute to cognitive impairments and positive symptoms characteristic of schizophrenia. To further examine the brain-wide impact of hippocampal disinhibition and the associated behavioural and cognitive changes, we combined ventral hippocampal infusion of the GABA-A antagonist picrotoxin with translational neural imaging and behavioural methods in rats. First, we used a conditioned emotional response paradigm to assess the impact of hippocampal disinhibition on aversive conditioning and salience modulation in the form of latent inhibition (chapter 2), both of which have been reported to be disrupted in schizophrenia. These experiments demonstrated hippocampal disinhibition caused disrupted cue and contextual fear conditioning, whilst we found no evidence that hippocampal disinhibition affects salience modulation as reflected by latent inhibition of fear conditioning. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing at hippocampal projection sites. Second, we used SPECT imaging to map changes in brain-wide activation patterns caused by hippocampal GABA dysfunction (chapter 3). SPECT experiments revealed increased neural activation around the infusion site in the ventral hippocampus, resembling metabolic hippocampal hyperactivity consistently reported in schizophrenia. In contrast, activation in the dorsal hippocampus was significantly reduced. This resembles the finding of anterior hippocampal hyperactivity coupled with reduced posterior hippocampal activation in patients with schizophrenia. Hippocampal disinhibition also caused marked extra-hippocampal activation changes in neocortical and subcortical sites, including sites implicated in fear learning and anxiety such as the medial prefrontal cortex (mPFC), septum, lateral hypothalamus and extended amygdala which may contribute to the disruption of fear conditioning demonstrated in chapter 2. Importantly, increased activation in the mPFC corresponds with previously reported prefrontal-dependent attentional deficits caused by hippocampal disinhibition. Third, to complement these findings we used magnetic resonance spectroscopy (MRS) to determine the effects of hippocampal disinhibition on neuro-metabolites within the mPFC (chapter 4). Using MRS, we demonstrated that hippocampal disinhibition causes metabolic changes in the mPFC, reflected by increased myo-inositol and reduced GABA concentrations. Overall, our results demonstrate ventral hippocampal disinhibition causes regional metabolic hyperactivity, supporting a causal role between GABA dysfunction and increased anterior hippocampal activity. In addition, hippocampal disinhibition causes activation and metabolic changes at distal sites, which may contribute to clinically relevant behavioural deficits, including impaired aversive conditioning, as demonstrated in our behavioural studies

Anatomical and computational models of the role of phasic dopamine signaling in intracranial self-stimulation: psychophysical and electrochemical tests

Dopamine (DA) neurotransmission is heavily implicated in electrical intracranial self-stimulation (eICSS), operant performance aimed at triggering stimulation of certain brain regions. To study the underpinnings of reward seeking, we combined ICSS with fast-scan cyclic voltammetry (FSCV), a means of monitoring stimulation-induced DA transients. Chapter one examines the circuitry linking midbrain DA neurons to the non-DA neurons recruited at the tip of a medial forebrain bundle (MFB) eICSS electrode. We found that unilateral, electrical, MFB stimulation evoked bilateral DA transients and that DA activation occurred, in large part, through polysynaptic circuitry. The series-circuit hypothesis is the focus of chapter two. On that view, the signal representing the intensity of the stimulation-induced rewarding effect must pass obligatorily through midbrain DA neurons. We found that the the DAergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) cannot serve as a unique link that relays the reward signal underlying eICSS of the MFB to later stages of the circuitry underlying reward seeking. The last chapter addresses the dominant theory linking phasic DA signalling to learning. On that view, DA transients signal the discrepancy between expected and experienced rewards and adjust synaptic weights to update reward predictions and bias action selection. Several of our findings are difficult to reconcile with the DA-RPE hypothesis. Recent technological advances have provided tools for studying the neural bases of reward seeking that are unprecedented in their power and number. It is important to extend this level of sophistication to our electrochemical and behavioural methods