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The substantia nigra pars reticulata (SNr) is an output nucleus of the basal ganglia, a group of neuronal circuits important for movement. According to a widely recognised model of the functional organisation of basal ganglia circuits, GABAergic SNr neurons contribute to action selection and execution through decreasing their firing rates and thus, disinhibiting their targets in the thalamus, midbrain and/or brainstem. Nonetheless, significant increases in SNr neuron firing rates have been reported during different motor behaviours in non-human primates and songbirds. Furthermore, it has been suggested that SNr neurons might not only encode for and control movement execution, but also movement preparation. Despite recent advances, relatively little is known about how SNr neurons function in rodents to control movement. To elucidate the functional role of SNr in motor behaviours, I first developed a novel delayed-Go task for head-fixed mice that incorporates aspects of both movement preparation and execution. I then used combinations of optogenetics and electrophysiology to manipulate and/or monitor the activity of GABAergic SNr neurons during different moments of the task. In the delayed-Go task, mice were first exposed to an auditory Delay Cue, and after a variable period (Delay Window) in which mice had to refrain from licking, they had to respond to a visual Action Cue by licking a spout to collect a water reward. Trial outcomes included 'Hit' (licked in good time in response to the Action Cue), 'Premature Hit' (inappropriately licked during the Delay Window) and 'Miss' (failed to lick in response to Action Cue). Mice learned to perform the delayed-Go task to satisfactory levels of success (i.e., acceptable rates of Hit trials) in about two weeks of non-consecutive daily sessions. Optogenetically-driving SNr neurons during the Action Cues of Hit trials delayed the reaction time to move (first licks). However, reaction times were shortened in Premature Hit and Hit trials when SNr neurons were optogenetically-driven during specific phases of movement preparation (Delay Cue and Delay Window, respectively). Overall, optogenetic manipulations showed that SNr neuron activity has a causal impact on movement preparation and execution. Electrophysiological recordings revealed that, in Hit trials, many SNr neurons engage in firing-rate modulations around the time of Action Cue and movement onset. Critically, these modulations mainly consisted of increased firing rates. Examination of SNr neuron activity in Premature Hit and Miss trials helped disambiguate the encoding of movement vs. cues. Irrespective of trial type, SNr neurons did not show the 'ramping up' activity that is typical of neurons encoding motor preparation. Overall, electrophysiological recordings suggest that most SNr neurons encode the execution of, but not preparation for, licking movements by increasing their firing rates. In conclusion, my investigations do not support classical models that posit appropriately-timed decreases in the activity of many SNr neurons as the fundamental mechanism that allows movement execution to occur. Furthermore, my studies do not provide evidence of SNr neurons encoding motor preparation with changes in firing rates. Finally, my research suggests that the causal impact of SNr neuron activity on movement depends on context, that is, whether an animal is preparing to move or is executing movement.

Characterising the function of the brain in health is critical if the changes that occur during disease states are to be fully understood. This is particularly true of the midbrain dopaminergic system, which is compromised in disorders such as Parkinson's disease and drug addiction. Much research concerning the midbrain dopaminergic system focuses on the two largest cell groups, namely those situated in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Caudal of the SNc and VTA is the third, relatively understudied group of dopaminergic neurons in the retrorubral field (RRF). The overarching goal of my thesis work was to characterise the function of RRF dopaminergic neurons in the mouse, in terms of their molecular makeup, connectivity and electrophysiological activity. Molecular markers expressed by RRF dopaminergic neurons shared features of both the SNc and VTA. Like the SNc, some neurons in the RRF express Sox6 but lack Otx2; like the VTA, some neurons in the RRF express calbindin-1 and calretinin. Moreover, I determined that while many RRF dopaminergic neurons express calbindin-1 and few express aldehyde dehydrogenase 1a1, the opposite is true for the caudal SNc. Thus, this combination of molecular markers is useful for delineating the border between the rostral RRF and caudal SNc. Intermingled amongst dopaminergic neurons in the RRF were many putative GABAergic and other non-dopaminergic neurons, indicating a diversity of cell types within this region. Cell type-selective anterograde and retrograde tracing of RRF dopaminergic neurons revealed their brain-wide connectivity. Examination of axonal projections uncovered a dense innervation of the ventrolateral striatum (VLS) and interstitial nucleus of the posterior limb of the anterior commissure (IPAC), in addition to a sparse innervation of the dorsolateral striatum (DLS) and olfactory tubercle. Although the projections of RRF dopaminergic neurons share features of both the nigrostriatal and mesolimbic pathways, the prominence of projections in ventral forebrain structures suggests that RRF neurons contribute more to the mesolimbic pathway. I observed that neurons providing monosynaptic inputs to RRF dopaminergic neurons are located in many brain regions. The densest clusters of input neurons were located in the bed nucleus of the stria terminalis (BNST), IPAC, and central amygdala. Overall, the results of these tracing experiments indicate that while the axonal projections of RRF dopaminergic neurons terminate in the striatum, their most prominent inputs arise from the extended amygdala. In the case of the IPAC, there appears to be prominent reciprocal connectivity with RRF dopaminergic neurons. Electrophysiological in vivo recording experiments demonstrated that the spontaneous firing properties of identified RRF dopaminergic neurons are broadly similar to their counterparts in SNc and VTA, specifically a slow firing rate (< 10 spikes/s) and relatively long action potential duration (> 1 ms). Foot shocks applied to the hindpaw induced a brief pause (∼220 ms) in the firing of both identified RRF and SNc dopaminergic neurons, followed by rebound activation. Together, the results from these electrophysiological recordings demonstrate that the firing properties of dopaminergic neurons in the RRF are typical of midbrain dopaminergic neurons and that they are equipped to represent aversive stimuli with a pause in firing activity. Next, I used an optogenetic approach to mimic the brief pause in firing observed in response to foot shock. Anaesthetised in vivo electrophysiological validation experiments demonstrated that ArchT-transduced dopaminergic neurons reliably pause their firing in response to brief (250 ms), physiologically-relevant yellow laser pulses. In freely-moving mice, 'positive control' experiments in which VTA dopaminergic neurons were briefly (250 ms) paused did not induce place aversion in either a bias conditioned place preference test or real-time place preference test. Collectively, the work in this thesis provides important new information on the substrates for RRF dopaminergic neuron function. I have shown that the functional properties of these neurons are partly overlapping with respect to neighbouring SNc and VTA dopaminergic neurons, in terms of molecular makeup, connectivity and electrophysiological activity. I conclude that RRF dopaminergic neurons are equipped to fulfil distinct and specialised roles in the brain as compared to their midbrain counterparts.

Many of the decisions we make in our day-to-day lives are influenced by internal physiological states and external environmental factors. In my thesis, I employed an interdisciplinary approach to investigate how internal physiological states, such as hunger, affect various aspects of decision-making. Neurobiological research has shown that food deprivation enhances dopaminergic signalling and increases the incentive salience of food. However, classical reinforcement learning theory only maps learning of external factors onto dopaminergic signalling. I extended the reinforcement learning theory in a biologically relevant manner to incorporate mechanisms by which internal physiological signals interact with the dopaminergic system to influence learning and action selection (chapter 3). This new theory predicts that food deprivation enhances learning, promotes approach behaviour, and reduces avoidance behaviour by enhancing the dopaminergic activation and teaching signals. I tested these theoretical predictions for decision-making in human volunteers. This study showed that hunger increased the valuation of food, but not of monetary rewards or nonfood items (chapter 4). Hunger reduced the biases for approach and avoidance behaviour that sated people exhibit by modulating the trade-off between positive and negative consequences of actions (chapter 5). Hunger also interacted with economic choice, but only when outcomes of choices had to be learned, not when they were explicitly described (chapter 6). Lastly, this study showed that hunger enhanced the reliance of "gut-instinct", without affecting cognitive control (chapter 7). In summary, this thesis characterises mechanisms by which motivational drives, such as hunger, could affect valuation, learning, and action selection in a biological manner. It provides empirical evidence that hunger also affects decision-making for monetary rewards, which could have significant implications for both real-world economic transactions and for aberrant decision-making in eating disorders and obesity.

Understanding the nature and consequences of information flow between the basal ganglia, cerebellum, thalamus and motor cortex on the acquisition and execution of motor skills may lead to better circuit therapies for brain disorders. Although basal ganglia and cerebellar output is thought to influence motor cortex activity via projections arising from distinct zones of ventral ‘motor’ thalamic nuclei (ventral medial [VM], ventral anterior [VA] and ventral lateral [VL] nuclei), the consequences of their activity on motor skills in rodents remains uncertain. Here, we first utilise an anterograde transsynaptic viral strategy to confirm that anatomically and functionally distinct basal ganglia-recipient and cerebellar-recipient neuron populations exist in the mouse motor thalamus. To address the behavioural significance of these two neuron populations for motor skill learning, Vglut2-Cre mice with either targeted chronic motor thalamus silencing (using overexpression of the inward-rectifier potassium channel Kir2.1) or acute optogenetic silencing of VM or VL (using the light-sensitive proton pump ArchT) thalamus were trained in a novel operant task monitoring the self-paced acquisition of a covert, temporally-constrained lever press sequence (fixed ratio of 3 lever presses within 2 seconds [FR3/2s]) over multiple sessions. Surprisingly, rather than causing gross motor impairment or impaired acquisition of the FR3/2s action pattern, mice receiving acute VM-ArchT silencing or chronic motor thalamus silencing showed faster early learning of the sequence compared to controls or VL-ArchT silencing. Simultaneous adaptation of peak within-press acceleration with learning was deficient in mice receiving VL-ArchT silencing. Our results suggest that manipulating the motor thalamus in mice can alter the pattern of within-day and between-day performance gains during task acquisition, potentially via downstream network effects which promote learning occurring via competing circuits.

The reciprocally-connected network of neurons of the subthalamic nucleus (STN) and globus pallidus (GP) plays a pivotal role in basal ganglia function and dysfunction. A series of in vivo and in vitro electrophysiological studies were performed in order to elucidate the mechanisms underlying activity in the STN-GP network. To characterise the relationship of activity in the normal STN-GP network to activity in the cerebral cortex, the principal excitatory afferent of the basal ganglia, single and multiple unit activity in STN and/or GP were recorded together with cortical electroencephalogram in anaesthetised rats during various states of cortical activation and inactivation. The data suggested that: (1) the rate and pattern of firing of STN and GP neurons are intimately related to coincident cortical activity and hence, the sleep-wake cycle; (2) oscillatory activity in the STN-GP network in health and disease may be driven by the cortex; and (3) activity of the network is regulated in space and time in a complex manner. To provide insight as to whether the relationship between the STN-GP network and the cortex is altered in Parkinson's disease (PD), a similar study was undertaken using a well established model of experimental PD, the unilateral 6-hydroxydopamine-lesioned rat. The results indicated that: (1) activity in the STN-GP network is dramatically altered by the chronic loss of dopamine from the forebrain; (2) the impact of the cortex on the network is modulated by dopamine and thus, pathological oscillatory activity in the basal ganglia in PD may be caused by the inappropriate processing of rhythmic cortical input; (3) the classical indirect pathway is abnormally augmented during activation of the parkinsonian brain; and (4) the relative contributions of firing rate and pattern to information coding in the STN-GP network and the basal ganglia is related to the state of cortical activation. To examine the dynamics of GABAergic inhibition in the STN and to test whether GABAA receptor-mediated synaptic input from the GP could generate rebound burst-firing in STN neurons, a phenomenon which may contribute to normal and abnormal activity in the STN-GP network, the equilibrium potential of GABAAreceptor-mediated current, the reversal potential of GABAA receptor-mediated inhibitory post-synaptic potentials, and the degree of membrane hyperpolarisation required for rebound burst-firing were determined using perforated patch-clamp recordings in vitro. An extension of this study investigated the responses of STN neurons to different patterns of inhibitory synaptic input. The findings implied that: (1) active chloride homeostasis ensures a large net driving force for GABAA receptor-mediated events in STN neurons; (2) asynchronous and irregular inhibitory input from the GP has a profound influence on activity in the STN; and (3) synchronous, bursting activity in the parkinsonian GP could contribute to pathological oscillatory activity in the BG by generating rebound burst-firing in STN neurons. In conclusion, the three studies have identified a number of key mechanisms underlying the activity of the STN-GP network. The importance of the corticosubthalamic projection in driving the activity of the STN-GP network has been established, suggesting that the STN should not be viewed as a simple relay station along the indirect pathway, but rather as a second important entry point for cortical information in the basal ganglia. Furthermore, the activity of STN and GP neurons was coupled, albeit to varying degrees, and thus, the reciprocal connections between these neurons are of great importance in shaping the activity of the network.

The midbrain dopamine system is involved in many aspects of purposeful behaviour and, when compromised, can have devastating effects on movement and cognition as seen in diseases like Parkinson's. In the healthy brain, dopamine neurons are thought to play particularly important roles in learning by signalling errors in reward prediction. The objective of this thesis was to investigate the diversity in the functional properties of the midbrain dopamine system, and how this is altered through genetic variation of relevance to Parkinson's and development of cell phenotype. This objective was addressed with a combination of behavioural experiments, in vivo single-cell recording and labelling (both in anaesthetised as well as awake rodents), immunofluorescence labelling, retrograde tracing and stereology. In a first set of experiments, it was demonstrated that chronic as well as acute genetic challenges can alter the firing patterns of midbrain dopamine neurons. Using a novel bacterial artificial chromosome-transgenic rat model, it was shown that the R1441C mutation in human leucine-rich repeat kinase 2, which is linked to Parkinson's, leads to motor deficits and an age-dependent reduction in the in vivo firing variability and burst firing of substantia nigra pars compacta (SNc) dopamine neurons. These findings help reveal processes of early, pre-degenerative dysfunction in dopamine neurons in Parkinson's. Similar effects on firing variability and burst firing of SNc dopamine neurons were found in a mouse model with conditional knock- out of the transcription factors Forkhead box A1 and A2 (FoxA1/2) in midbrain dopamine neurons. These findings indicate that FoxA1/2 are not only crucial for the early development of dopamine neurons, but also their function in the mature brain. In a second set of experiments in wildtype mice, it was demonstrated that midbrain dopamine neurons (located in SNc and ventral tegmental area) show diverse expression of the molecular markers Calbindin, Calretinin, Aldh1a1, Sox6, Girk2, SatB1 and Otx2. It was found that selective expression of these markers is of use for discriminating between midbrain dopamine neurons that project to dorsal striatum or nucleus accumbens. To elucidate whether the diverse molecular marker expression would map onto dopamine neurons whose firing correlates with distinct behavioural events, midbrain dopamine neurons were recorded and labelled in head-fixed awake mice either exposed to neutral sensory stimuli or performing a classical conditioning paradigm. The population activity of midbrain dopamine neurons was not modulated by neutral sensory stimuli. Interestingly, fewer than 50&percnt; of identified dopamine neurons showed phasic firing increases following reward- predicting cue and/or reward delivery, despite the common assumption that most (if not all) midbrain dopamine neurons signal reward prediction errors. Instead, firing was modulated by other explanatory factors, such as licking, or showed no modulation during the task. Response types of midbrain dopamine neurons were not correlated with their anatomical location nor the selective or combinatorial expression of the markers Aldh1a1, Calbindin and Sox6. In conclusion, the first set of experiments identified how different genetic burdens can alter the in vivo firing of midbrain dopamine neurons, and provide new insights into how circuits can change in pathological or compensatory ways at early disease stages in Parkinson's. The second set of experiments revealed striking heterogeneity of midbrain dopamine neurons in the intact system, and established further a functional diversity in the response types of identified midbrain dopamine neurons that is only partially consistent with canonical reward prediction error signalling.

The striatum is the largest nucleus of the basal ganglia, and acts as a point of convergence for thalamic, cortical and midbrain inputs. It is involved in both motor and associative forms of learning, and is composed of spiny projection neurons (SPNs) whose output along the so-called "direct pathway" and "indirect pathway" is modified by the activity of diverse sets of interneurons. Four "classical" or major classes of striatal interneuron can be identified according to the selective expression of the molecular markers parvalbumin (PV), calretinin (CR), nitric oxide synthase (NOS) or choline acetyltransferase (ChAT). Although the interneurons within a class are generally considered to be homogeneous in form and function, there is emerging evidence that some classes encompass multiple types of neuron, and that the heterogeneity in striatal interneurons extends beyond these four classes. Defining the extent of interneuron heterogeneity is important for understanding how the striatum processes distinct, topographically-organized inputs from the cortex and thalamus in order to govern a wide range of behaviors. To address these issues, a combination of immunofluorescence microscopy and stereological cell counting approaches was used in striatal tissue from rat, mouse and non-human primate. This was supplemented by in vivo recording and juxtacellular labelling of single neurons in rat. A first set of experiments showed that secretagogin (Scgn), a calcium-binding protein, is expressed by a large number of interneurons in the dorsal striatum of rat and primate, but not in the mouse. In all species tested, secretagogin was expressed by a subset of PV+ interneurons and a subset of CR+ interneurons in the dorsal striatum, but also labelled a group of interneurons that did not express any of the classical markers of striatal interneurons. A second set of experiments in the rat demonstrated that the selective co-expression of Scgn by PV+ interneurons delineates two topographically-, physiologically- and morphologically-distinct cell populations. These topographical differences in distribution were largely conserved in the primate caudate/putamen. In rats, PV+/Scgn+ and PV+/Scgn- interneurons differed significantly in their firing rates, firing patterns and phase-locking to cortical oscillations. The axons of PV+/Scgn+ interneurons were more likely to form appositions with the somata of direct pathway SPNs than indirect pathway SPNs, whereas the opposite was true for the axons of PV+/Scgn- interneurons. These two populations of GABAergic interneurons provide a potential substrate through which either of the striatal output pathways can be rapidly and selectively inhibited, and in turn mediate the expression of behavioral routines. A third set of experiments showed that CR+ interneurons of the dorsal striatum can be separated into three populations based on their molecular, topographical and morphological properties. Small-sized ("Type 3") CR+ interneurons co-expressed Scgn and were restricted in their distribution towards the rostro-medial poles of the striatum in both rats and primates. In rats, these neurons also expressed the transcription factor SP8, suggesting that they may be newly generated throughout adulthood. Large-sized, ("Type 1") CR+ interneurons did not express Scgn, but could be further distinguished by their expression of the transcription factor Lhx7. Medium-sized ("Type 2") CR+ interneurons did not express Scgn or Lhx7, and had heterogeneous electrophysiological properties in vivo. The expression of Scgn, but not other classical interneuron markers, identified a group of interneurons that were restricted in their distribution towards the ventro-medial aspects of the dorsal striatum. A fourth set of experiments showed that these neurons are also present in the core and the shell of the nucleus accumbens. Unlike the case of dorsal striatum, however, PV+ interneurons and CR+ interneurons of the nucleus accumbens did not co-express Scgn. Moreover, many of the interneuron populations studied had greater densities in the ventral striatum compared to the dorsal striatum, and had quantifiably strong biases in their distribution towards a variety of axes within both the core and the shell of the nucleus accumbens. These data thus highlight some major differences in the constituent elements of the microcircuits of dorsal striatum and nucleus accumbens. In conclusion, these studies have revealed a great deal of molecular, topographical, electrophysiological and structural heterogeneity within the interneuron populations of the striatum. As several of these interneuron populations were not evenly distributed throughout the striatum, this ultimately suggests that the microcircuit of the striatum is specialized according to regions that differ in their cortical, thalamic and dopaminergic inputs.

Use-dependent long-term plasticity in synaptic connections represents the cellular substrate for learning and memory. The hippocampus is the most thoroughly investigated brain area for long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) are both well characterized in glutamatergic excitatory connections between hippocampal principal cells in vitro and in vivo. An increasing number of studies based on acute brain slice preparations report LTP and LTD in excitatory synapses onto postsynaptic hippocampal GABAergic inhibitory interneurons. However, a systematic study of activity-induced long-term plasticity in excitatory synaptic connections to inhibitory GABAergic interneurons in vivo is missing. To determine whether LTP and LTD occur in excitatory synaptic connections to the hippocampal CA1 area GABAergic interneurons types in intact brain, I have used juxtacellular recording to measure synaptically evoked short-delay postsynaptic action potential probability in identified CA1 neurons in the urethane-anaesthetized rats. Plasticity in excitatory synaptic connections to CA1 cell types was measured as a change of afferent pathway stimulation-evoked postsynaptic spike probability and delay. In the study only experiments with monosynaptic-like short-delay (range 3-12 ms) postsynaptic spikes phase-locked to afferent stimulation were used. Afferent fibres were stimulated from the CA1 area of the hippocampus at the contralateral (left) side to avoid simultaneous monosynaptic activation of GABAergic fibres and to exclude antidromic spikes in recorded CA1 cells (in right hemisphere). Plasticity in pathways was tested using theta-burst high-frequency stimulation (TBS, 100 pulses), which is one of the most common synaptic plasticity induction protocols in acute brain slice studies. I discovered that TBS elicited permanent potentiation in single shock-evoked postsynaptic spike probability with shortening or no change in evoked spike latency in various postsynaptic neuron types including three identified pyramidal cells and parvalbumin-expressing (PV&plus;) interneurons. Most fast-spiking PV+ cells showed LTP including an axo-axonic cell and one bistratified cell, whereas two identified basket cells exhibited LTD in similar experimental conditions. In addition, I discovered diverse plasticity in non-fast spiking interneurons, reporting LTP in an ivy cell, and LTD in three incompletely identified regular-spiking CA1 interneurons. I report that the underlying brain state, defined as theta oscillation (3-6 Hz) or non-theta in local field potential, failed to explain whether LTP, LTD or no plasticity was generated in interneurons. The results show that activity-induced potentiation and depression similar to LTP and LTD also occur in excitatory synaptic pathways to various CA1 interneurons types in vivo. I propose that long-term plasticity in excitatory connections to inhibitory interneurons may be take place in learning and memory processes in the hippocampus.

Central to the understanding of memory is a detailed understanding of the processes contributing to how some information is retained as memories, yet other information is not. Relevant to this is the question, does value and saliency information coded by dopaminergic neurons of the ventral tegmental area (VTA) affect hippocampal memory function and how might this arise? In order to address this question, I performed large scale extracellular recordings combined with optogenetic activation of dopaminergic neurons in mice. Tetrodes were located in the VTA and pyramidal cell layer of the CA1 subfield of the dorsal hippocampus. Midbrain dopaminergic neurons were made to express a chimeric protein formed of the light activated ion channel channelrhodopsin-2 and enhanced yellow florescent protein (ChR2-eYFP) through injection of a Cre activated viral construct in the VTA of DAT-IRES-Cre+/- mice. Mice explored familiar and novel open fields in the presence or absence of photostimulation. Periods of sleep and rest were recorded before and after each exploration in order to calculate the reactivation strength of hippocampal waking firing activity during subsequent sleep; a process thought to aid the stabilisation of representations enhancing their retention as memories. ChR2-eYFP expressing axons were present in the dorsal hippocampus demonstrating a direct dopaminergic projection from the midbrain to the hippocampus. Units isolated from midbrain tetrodes showed a sustained increase in mean firing rate during exploration of a novel over a familiar environment, indicating they have the potential to drive sustained dopamine release in target structures in response to such a sustained novelty cue. Hippocampal reactivation strength after exploration of a novel environment was higher than that seen after exploration of a familiar environment and this was further enhanced by burst mode photoactivation of dopaminergic neurons at their cell bodies in the VTA or at the afferent dopaminergic fibres in the dorsal CA1. A second group of mice performed a spatial learning task on a maze dubbed the 'crossword maze'. Photostimulation during learning trials did not increase the rate of learning but it did increase performance in a probe test held one hour after the end of the learning trials. Additionally, there was enhanced reinstatement of the hippocampal spatial representation during the probe test and it was preceded by enhanced reactivation of the newly formed representation in the intervening rest period. These findings reveal that midbrain dopaminergic neurons, encoding salient information about an environment, promote hippocampal network dynamics associated with memory persistence, thus modulating hippocampal memory function according to the value of the information to be remembered.

The striatum is the major input structure of the basal ganglia, and is composed of two major populations of spiny projection neurons (MSNs), which give rise to the socalled direct and indirect pathways, and several types of interneuron. Dopaminergic inputs to striatum are critical for its proper function. Indeed, loss of dopaminergic neurons in Parkinsonism leads to motor disturbances, grossly disturbs striatal activity, and is associated with the emergence of excessively-synchronized network oscillations at beta frequencies (15-30 Hz) throughout the basal ganglia. How the distinct structural, neurochemical and other properties of striatal neurons are reflected in their firing rates and patterns in vivo is poorly defined, as are their possible cell-type-selective contributions to the aberrant oscillations arising in the Parkinsonian brain. To address these issues, I first used multi-electrode arrays to record the spontaneous firing of ensembles of neurons in dorsal striatum in both anaesthetised dopamine-intact and Parkinsonian (6-hydroxydopamine-lesioned) rats during two well-defined brain states, slow-wave activity (SWA) and spontaneous activation. The chronic loss of dopamine led to an overall increase in the average firing rates of striatal neurons, irrespective of brain state. However, many neurons in the Parkinsonian striatum still exhibited the low firing rates and irregular firing patterns typical of neurons in the dopamine-intact striatum. During SWA in Parkinsonian rats, the firing of striatal neurons was more strongly synchronized at low frequencies, in time with cortical slow (~1 Hz) oscillations. During spontaneous cortical activation in Parkinsonian rats, more striatal neurons engaged in synchronized firing in time with cortical beta oscillations. Under the same experimental conditions, I then recorded the spontaneous firing of individual striatal neurons and juxtacellularly labelled the same neurons to verify their cell types, and locations; indirect pathway and direct pathway MSNs were distinguished by the expression (and lack of expression respectively), of the neuropeptide precursor preproenkephalin (PPE). After chronic dopamine loss, and on average, only indirect pathway (PPE+) MSNs significantly increased their firing rates during both brain states, and engaged in widespread, synchronized firing in the beta-frequency range. This did not hold true for all PPE+ MSNs; the Parkinsonian striatum contained many MSNs that were virtually quiescent, which were just as likely to belong to the indirect pathway as the direct pathway. Direct pathway (PPE-) MSNs increased their firing only during SWA after chronic dopamine loss and rarely engaged in aberrant beta oscillations. Taken together, these data suggest that (1) the firing patterns, as well as the firing rates of many striatal neurons are grossly disturbed by chronic loss of dopamine and (2) that the pathological synchronization of the rhythmic firing of a subpopulation of indirect pathway MSNs could contribute to the propagation of aberrant beta-frequency oscillations to downstream basal ganglia nuclei in Parkinsonism.