Physio 21 - Basal Ganglia PDF

Pag. 1 a 21 PHYSIO 21 – BASAL GANGLIA 1.​ Overview of the basal ganglia and their circuit The basal ganglia are usually paired with the cerebellum, since they are the controllers of functions - not only constrained to movement, but also to cognitive functions. “Basal ganglia” is a definition...

Pag. 1 a 21 PHYSIO 21 – BASAL GANGLIA 1.​ Overview of the basal ganglia and their circuit The basal ganglia are usually paired with the cerebellum, since they are the controllers of functions - not only constrained to movement, but also to cognitive functions. “Basal ganglia” is a definition related to the brain nuclei located deep in the telencephalic white matter. The system of basal ganglia refers to the connection of the proper basal ganglia with other structures. The system does not only include all the brain nuclei functionally related to basal ganglia (the globus pallidus, the putamen, and the striatum), but also all the connections of the system. Indeed, the circuit includes also: ​ The thalamus (ventral anterior and lateral thalamic nuclei) ​ The subthalamic nucleus, sometimes considered a proper part of the basal ganglia ​ The substantia nigra, composed of: o​ a pars compacta o​ a pars reticularis they perform different tasks (the same is for the red nucleus, having a magnocellularis and a parvocellularis portion). The two parts of the substantia nigra are both connected to the basal ganglia, but with completely different functions. The origin and target of the basal ganglia system is the cortex. 2.​ Basal ganglia anatomy and function Similarly to the cerebellum, the anatomy of the basal ganglia is related to their function: this group of nuclei modulates the activity of the cortex. Studies on this structure of the brain (and their motor functions) are largely based on pathology. There are lots of studies also based on recording of healthy systems on animal models (as for the cerebellum),  Pag. 2 a 21 but the studies giving evidence on the overall function of the basal ganglia in movement and cognitive functions are the ones done on lesions. Similarly to cerebellum, damages to the basal ganglia cause neuronal deficits that have common features (the common features for the cerebellum were loss of speed and fluency: apotonia, ataxia and tremor). A problem to the basal ganglia generally implies that there’s either a deficit or an excess in movement. Whatever is the pathology (e.g., Parkinson’s disease or Huntington’s disease), there is a common feature: either there’s an uncontrolled excess of movement or there’s an absence or a clear deficit in the overall excitability of the motor system. Problems to the basal ganglia do not imply a deficit of a specific function but are related to the overall control of function. Motor features exhibit both gain of function (overactive movements: dyskinesia) and loss of function (loss of voluntary movement: akinesia). The cerebellum is a clock (motor, but not only, since it is also involved in cognitive functions) since the timing of an action (the timing of activation of the muscles) is impaired in its lesions. Cerebellar lesions cause loss of fluency and coordination, pendular reflex, dysarthria, deficit in performing alternate movements and tremor. These are deficits induced by the lack of temporal proper coordination (the time course of the movement), that impairs its precision (in time and of the movement itself) and fluency. Considering the deficits of the basal ganglia, normally they are characterised by either the excess or the deficit of the movement. The motor features include: ​ Gain of function: overactive and unwanted movement - dyskinesia (a deficit due to an uncontrolled movement) ​ Loss of function (loss of movement): its extreme consequence is akinesia (meaning loss of kinesis, so loss of movement) Although motor control may be a dominant feature of the basal ganglia, it’s not the only one. The involvement of the basal ganglia system in behaviour, higher cognitive functions, emotions, and mood is even more relevant than for the cerebellum. Basal ganglia pathology is also associated to higher-order aspects of behaviour, involving emotion, reward, executive functions, and mood. These are higher order aspects of the cortical computation (the emotions, mood and mental states intended as cognitive functions). This is why patients with basal ganglia lesions or diseases end up having neuropsychiatric or cognitive disorders. Neuropsychiatric disorders are probably due to the huge correlation between the basal ganglia and the prefrontal cortex. The prefrontal cortex is an associative cortex, highly related to executive functions, receiving a very important input from neurotransmitters coming from the brainstem. These two features end up in impairing neuropsychological and neuropsychiatric functions.  Pag. 3 a 21 Although there are lots of scientific efforts to understand the final functions of basal ganglia and the processes underlining them, they remain one of the most poorly understood areas of the brain, for the same reason the cerebellum is not a clearly understood area. Indeed, there is a module, a loop, and connections; and even if there are explanations of the way the different areas talk to each other, the function of this loop is still not clear. Even if the stereotyped process (the loop between basal ganglia and cortex) is understood, it’s not function is not completely understood. Basal ganglia may more generally be involved in action selection. This picture is not complete, it was drawn to explain the descending system from the cortex (understand who is talking with the cortex when it computes the motor program that is then executed by the spinal cord). It’s not precise since the connections between the cerebellum and the brainstem and spinal cord are lacking, however it’s clear in depicting the basal ganglia relationships. The basal ganglia talk to the cortex: their input and output is always the cortex. Medial and lateral view of a macaque cortex (the prefrontal portion, the temporal and parietal lobes are much more developed in humans). Basal ganglia-thalamocortical circuits project to 4 distinct cortical regions, all in the frontal lobe: ​ Motor (green in picture): M1, SMA, premotor cortex ​ Oculomotor (purple): frontal eye fields (FEF, SEF) ​ Prefrontal (brown): prefrontal cortex (PFC) ​ Limbic (blue): anterior cingulate (AC) and orbitofrontal (OF) cortex Motor areas in the frontal lobe include the primary motor area (motor proper area M1), the nonprimary motor areas (in the medial surface are called SMA or pre-SMA). In the convexity, there are premotor dorsal and ventral areas. In the macaque, there’s a clear distinction between dorsal and ventral since there’s the arcuate sulcus, separating with a spur (not evident in the picture) the two areas of the premotor cortex (dorsal and ventral). It also separates the motor cortex with the frontal eye fields, that in monkeys are located in the frontal cortex, anterior to the motor area – but not as evident as in the macaque. The areas related to oculomotion (labelled in purple, not represented in the same colour as the motor ones in the picture) are separated from the motor areas, even though they are involved in motion – but they are moving eyes. Indeed, the complexity of the eye movement makes them autonomous and independent with respect to the rest of the motor cortex. The anterior cingulate area and the orbitofrontal cortex (blue) are areas more related to the limbic system. They are very visible on the medial surface, and not on the convexity.  Pag. 4 a 21 On the other hand, the convexity includes the proper prefrontal cortex (the dorsolateral prefrontal cortex) and the orbitofrontal cortex. In the picture, there are different labels because these areas make independent connections (tracts, pathways) with the basal ganglia. They connect with different portions of the striatum, and they receive from different areas of the thalamus and therefore represent independent loops. Therefore, basal ganglia are not a ‘pot’ containing mixed neurons serving large portions of the cortex. This is more evident in basal ganglia than the cerebellum (the lateral cerebellum is the newest – evolutionary speaking – area, involved in cognitive functions, emotions, and mood states). Basal ganglia, indeed, include independent loops connecting independent portions of the cortex, that are part of circuits of different functions. 4 basal ganglia loops can be identified: ​ Motor proper (skeletomotor) - fed by o​ primary motor o​ premotor and supplementary motor cortex o​ sensory cortices (also S1) Indeed, the motor areas are always connected to the sensory ones. So, the skeletomotor loop is fed by sensorymotor areas. Considering the frontal lobe, it’s mainly fed by the motor and the premotor areas (since they are located in the frontal lobe). ​ Oculomotor - fed by the frontal eye field. ​ Prefrontal loop - fed by the prefrontal cortex. ​ Limbic loop - the convexity of the orbitofrontal cortex is part of the prefrontal, whereas the medial portion is part of the limbic loop, connecting the medial orbitofrontal and the anterior cingulate area with the basal ganglia. -All the loops enter the basal ganglia system in different positions. The striatum is the entrance, and one big portion of it is dedicated to the motor loop -> computation (interaction) takes place in the basal ganglia -> circuit ends up in the thalamic nuclei and ultimately in the cortex.  Pag. 5 a 21 The oculomotor starts from the frontal eye fields (oculomotor areas) -> ends in the caudate, it enters -> computed by a different portion of the basal ganglia with respect to the motor -> uses other nuclei of the thalamus to go to the same areas. The same is true for the prefrontal, the executive associative loop, meaning the higher cognitive loop that performs executive functions in particular. This explains why sometimes we perform unvoluntary movements, not only due to the excess of the excitation of the cortex but maybe due to the involvement of the prefrontal area, that enters in the rostral caudate. Other territories of the basal ganglia include the nuclei of the thalamus back to the cortex. The limbic loop (involved in emotion and motivation) enters in the ventral striatum -> uses another portion of the basal ganglia -> ends in other thalamic nuclei. 3.​ Inputs and outputs The basal ganglia receive from the cortex and the thalamus (input) The main entrance is the striatum, and the second is the subthalamic nucleus. Inputs coming from the cortex and thalamus enter the main door (the striatum). Indeed, in order to enter the basal ganglia, it’s mandatory to enter in the striatum, however other areas can connect to the basal ganglia by means of the subthalamic nucleus. The basal ganglia output is the internal segment of the globus pallidus and the pars reticularis of the substantia nigra. Therefore, the pars reticularis of the substantia nigra must be considered as an extension of the internal pallidus (that is the output). This system exerts inhibition on the target (that is the thalamus and some brainstem nuclei). This inhibitory system is similar to the cerebellar Purkinje cells that inhibit the deep nuclei. The controllers of a certain function refine the program by using inhibition rather than excitation. This mechanism is similar to the process of pruning taking place in the first months of life (when there is an excess of synapses, that are not functional, and therefore are eliminated); so, the program is refined by deletion. The thalamus and part of the brainstem are the targets. This is simpler than the cerebellum, for which the targets were several (various brainstem areas, the thalamus, the cortex, and the spinal cord). The thalamus is the main target because it’s the route to the cortex. With very few exceptions (olfaction), the thalamus is a mandatory station to reach the cortex. To resume: ​ Inputs of the basal ganglia: from thalamus and cortex (mainly) to striatum and subthalamic nucleus. ​ Outputs: internal globus pallidus and substantia nigra reticularis. ​ Targets: thalamus and some portions of the brainstem.  Pag. 6 a 21 4.​ Basal ganglia pathways The general plan of the loop (that is the same for all 4 loops, each cortex talking to the basal ganglia), when entering the basal ganglia, can follow 2 possible directions: a direct and an undirect pathway. General plan of the direct loop The direct pathway (1)​ enters the basal ganglia through the striatum (wherever in it, since we are considering the general plan) -> (2)​ striatum projects directly to the internal pallidus and substantia nigra reticularis -> (3)​ to the thalamus -> (4)​ connect to the cortical areas (motor, etc). The output is ultimately excitatory to thalamo-cortical projections and therefore to cortex (globus pallidus internal is itself inhibited).  Pag. 7 a 21 General plan of the indirect loop The indirect pathway is indirect because there are some stations in between. (1)​ From the striatum -> (2)​ pathway enters the external pallidus -> (3)​ it goes to the subthalamic nucleus and finally to the internal pallidus (2 intermediate station) -> (4)​ reaches the thalamus -> (5)​ cortex. The output is ultimately inhibitory to thalamo-cortical projections, and therefore to cortex (globus pallidus internal is excited). These two pathways are not only different in terms of the number of synapses needed to reach the target but also in terms of the effect on the target. Indeed, the direct pathway is excitatory on the thalamus (on the thalamocortical projections). The thalamus targeted by the basal ganglia is projecting to the cortex; and the thalamocortical projections are excitatory over the cortex. So, in the end the direct pathway excites the thalamus. Given that the globus pallidus exerts an inhibition on the thalamus, the direct pathway removes the inhibition. This means that if the cortex excites the striatum, the striatum inhibits the globus pallidus internal (the output). The internal pallidus is itself an inhibitor of the thalamus. By inhibiting the inhibitor (removing the inhibition), the thalamus is activated. Summing up the direct pathway in the basal ganglia: Entering in the cortex, it excites the striatum that projects to the internal pallidus, inhibiting it. Given that the internal pallidus is the inhibitor of the thalamus, the inhibition is removed (the internal pallidus function is cancelled) and the thalamus can go to the cortex (excitatory connection, as if the gate is opened). There are two stations: the striatum and the internal pallidus. This mechanism (inhibition of inhibition) is similar to the cerebellar Purkinje cells, that exert an inhibition to the deep nuclei. If the deep nuclei didn’t receive any input from the mossy and climbing fibres, they wouldn’t be excited – and the Purkinje cells would exert an inhibition on silent neurons (that would be useless). The case of the basal ganglia is similar (the cortex acts on the striatum that acts on the globus pallidus, inhibiting the inhibitor). If the inhibitor is not talking, the way is already open, and its inhibition is not needed. To keep the door closed, the globus pallidus internal must exert an action on the thalamus (it’s actively closing it, it needs to be active). The globus pallidus internal has a background discharge, it is tonically active. The default situation is a block. The globus pallidus internal and substantia nigra reticularis exert a tonic inhibition on the thalamus. If the striatum acts on the globus pallidus, removing the inhibition, the thalamus is activated and can talk with the cortex. This is why the pathway is excitatory. Summing up the indirect pathway, It goes in an opposite direction and is different in terms of stations. It’s longer: the striatum projects to the external pallidus projects to the subthalamic nucleus in turn projects to the internal pallidus.  Pag. 8 a 21 The action of the subthalamic nucleus on the internal pallidus is excitatory. The striatum inhibits the external pallidus inhibiting the subthalamic nucleus exciting the internal pallidus. The striatum always wants to inhibit the globus pallidus (internal and external). When the striatum is excited, it inhibits them (and so, in the direct pathway it removes the inhibition since the globus pallidus is inhibiting the thalamus). In the indirect pathway, the striatum inhibits the internal pallidus that is inhibiting the subthalamic nucleus (that is excitatory on its target, the internal pallidus). At the end, there’s an increased inhibition of the thalamus (because the internal pallidus is excited). The internal and external globus pallidus and the subthalamic nucleus all have a background discharge, they are tonically active. The external pallidus inhibits the action of the subthalamic nucleus, that is exciting the internal pallidus. By removing the inhibition, the subthalamic is given more power. The subthalamic nucleus wants the internal globus pallidus to be stronger, and so to inhibit the thalamus. So, the indirect pathway ultimately inhibits the cortex. RECAP The direct pathway is also called excitatory pathway, while the indirect is the inhibitory one (because of the chain of neurons explained before); in the end, in the indirect pathway, the synapse that matters for the output is the positive (excitatory) one of the subthalamic nucleus on the internal globus pallidus, increasing the power of who is closing the door (exerting an inhibition). The direct pathway has only two stations in the basal ganglia (from the striatum: the internal pallidus and the substantia nigra reticularis; the target is the thalamus). The indirect pathway is more complex, since it has two additional stations, four in total (from the striatum: the external pallidus, the subthalamic nucleus and the internal pallidus). Also, the final effect on the pallidus internal is opposite: to strengthen its pathway. To understand this loop, note that there are structures that have a background discharge. In the same system, there are two pathways targeting the same structure, exerting opposite functions. So, who prevails and when? Why not having only one of the two structures, and modulate its activity? It’s because the brain always refines and increases its degrees of freedom. 5.​ Input and output of striatum (input) The afferent inputs are the main entrance door of the basal ganglia (the striatum) and include nearly all the cerebral cortex: -​ frontal lobe -​ somatosensory cortex -​ motor and prefrontal cortices -​ orbitofrontal cortex. Considering the motor (skeletomotor) loops, there’s a somatotopic and topographical organisation. The topographical organisation of the map of entrance in the basal ganglia implies that different portions of the cortex project to different portions of the basal ganglia (of the striatum). For instance, somatosensory and motor cortex enter the posterior putamen, whereas the prefrontal cortex enters the anterior caudate.  Pag. 9 a 21 There’s also a somatotopy of somatosensory and motor afferents. This organisation provides the basis for the segregation of different circuits. The cortex is not the only input to the basal ganglia. There are also: ​ Intralaminar and ventrolateral nuclei of the thalamus ​ Crosstalk within the striatum ​ The pars compacta of the substantia nigra Summing up, the inputs to the main entrance door of the basal ganglia (the striatum) are: ​ Large portions of the cortex, projecting with a topographical organisation on the striatum, separating different loops. Within the loops, there is also a somatotopic organisation. o​ frontal lobe o​ somatosensory cortex o​ motor and prefrontal cortices o​ orbitofrontal cortex. ​ Intralaminar (IL) and ventrolateral thalamic nucleus (VL) ​ The pars compacta of the SN (the pars reticularis is part of the basal ganglia output). There are large inputs from dopaminergic neurons of the pars compacta. ​ Cholinergic inputs form other large aspiny neurons ​ GABA inputs from spiny neurons and from interneurons. These two types of neurons are located in the striatum. Therefore, there can be connections within the stratum. (output) The striatum (inhibitory) output are the globus pallidus internal and the substantia nigra pars reticularis (reached directly with the direct pathway). In case of the indirect pathway, the globus pallidus external goes to the subthalamic nucleus that finally connects to output. Considering the cortical sources, the Brodmann area 4 (the primary motor cortex, purple in the picture below) is the main source, but also 1, 2 and 3 Brodmann areas. So, the somatosensory cortex is involved in the skeletomotor loop too, not only the motor areas. Cortico-striatal afferents These areas overlap on the areas of the striatum where they project. Each cortical area projects to several areas of the striatum, in the portion dedicated to the skeletomotor loop. So, the striatum is topographically and somatotopically organised.  Pag. 10 a 21 6.​ Medium spiny neuron The medium spiny neuron is the one projecting out. Note the architecture of the synapse occurring on this neuron, there are architectural maps: the cerebral cortex is projecting on the top of the dendrites. There are the medium spiny neurons in the striatum and large aspiny neurons (that are releasing different neurotransmitters) at the emergence of the dendrites. -​ The cerebral cortex releases glutamate on the striatum. -​ Medium spiny neurons use GABA, while large aspiny neurons use acetylcholine. -​ The substantia nigra (in green) uses dopamine and acts on the medium spiny neuron at midpoint from the emergence of the head of the dendrite. The substantia nigra is divided into 2 portions: ​ Pars compacta, that is an input to the striatum, releasing dopamine on it ​ Pars reticularis, that is the output of the basal ganglia The location of dopaminergic terminals onto the spiny neuron allows the dopaminergic input to modulate the efficacy of the cortical inputs to the striate nucleus. To look at the pattern of termination of afferents on the striatum, the medium spiny neurons are used because they are the most common type of neuron in the basal ganglia. They receive all types of inputs (both excitatory and inhibitory), they integrate lots of neurotransmitters and neuromodulators (respond to a wide variety of them). They give rise and receive the extrinsic connections (from outside the basal ganglia) and intrinsic connections (from local interneurons and other spiny neurons). Dopamine has a powerful modulating effect on synaptic transmission from the cortex to the medium spinal neurons.  Pag. 11 a 21 So, the architecture is very complex: -​ extrinsic signals (substantia nigra pars compacta, cortex, thalamus) usually arrive to the dendrites, -​ intrinsic signals are very powerful because they act near the soma. The thalamus releases glutamate that can act at the level of the spine or of the dendrite. Interneurons such as large aspiny interneurons releasing acetylcholine act at the level of the soma and the same is true for other interneurons releasing GABA. Parkinson disease is related to dopamine, released by the pars compacta of the substantia nigra and acting at the level of the striatum. It is interesting to see the role of dopamine on the basal ganglia. Looking at the cortex and thalamus, they excite the striatum with connections that have a sort of label (if they come from motor areas they are labelled as motor, if they come from frontal eye fields they are labelled as oculomotor, etc.), so the circuits coming from the cortex to the basal ganglia are known and the role of their excitation on the basal ganglia can be inferred. The problem is that the substantia nigra is a structure in the midbrain, it is a small structure and does not really have a specific function apparently, similarly to the inferior olivary nucleus in the cerebellum that seems to regulate the activity of the Purkinje cells more in a general way than for a specific function or activity. In the case of the substantia nigra pars compacta, dopamine has a powerful modulating effect on synaptic transmission from the cortex to the medium spinal neurons, but it is important to understand whether it favours the direct or indirect pathway. Looking at the image above, the intracellular recording from striatal medium neurons can be seen. There is a strong correlation between slow wave activity in the ECoG (electrocorticography) and the up-state of spiny striatal neurons, which means that these neurons are clearly connected with the cortex and this correlation reflects the fact that there is a synchrony between basal ganglia and cortex. 7.​ Types of spiny neurons in the striatum  Pag. 12 a 21 There are actually 2 types of spiny neurons, giving rise to the two types of pathways. Looking at the image, the striatum can be seen made of red and blue dots: -​ the red dots = neurons giving rise to direct pathway -​ the blue dots = originate the indirect pathway (external pallidus). So, there is here a labelled line code. The two types of neurons release GABA (are GABAergic), both for the direct and indirect pathway but this is helped by another neurotransmitter: -​ in the case of the direct pathway, it is substance P or dynorphin -​ in the case of the indirect is enkephalin (an internal opioid). So, the two chemically different populations of striatal medium spiny neurons are intermixed: -​ other population (red) projects to the globus pallidus internal segment and substantia nigra pars reticulata and contains GABA, dynorphin, and substance P. -​ one population (blue) projects to the globus pallidus external segment and contains GABA and enkephalin 8.​ Stations in the basal ganglia circuit The stations can be analysed step by step. 1.​ Starting from the subthalamic nucleus, that behaves like the striatum because it is also a door of access. The afferent inputs are not all the ones going to the striatum but only some of them: ​ Frontal cortex, in particular SMA, but also primary and premotor ​ Part of the frontal eye fields ​ External pallidus (thanks to the indirect line; this is an inhibitory projection). The subthalamic nucleus, therefore, receives also independently from the globus pallidus; it seems to be the back door mainly for the motor loop. The subthalamic, then, sends to internal pallidus and substantia nigra but also sends back to the external pallidus. 2.​ The internal pallidus is the output (for limb movements), it receives from the striatum (direct pathway) and subthalamic nucleus (indirect pathway). The effect is different because the subthalamic excites the pallidus while the striatum inhibits it and so here is the difference between the two pathways of the basal ganglia. The output is inhibitory on the ventrolateral (oral part) and ventralanterior (principal part) nuclei of the thalamus, but also other structures such as “midbrain extrapyramidal area” (which is the origin of the reticulospinal system) and intralaminar nuclei of the thalamus. Focusing on the ventrolateral and ventralanterior nuclei of the thalamus, they in turn project to primary motor, premotor, SMA, prefrontal cortex, so the globus pallidus is the output but not for every type of cortex because, for example, it is not involved in the circuit of the frontal eye field; this is the role of the substantia nigra pars reticularis. The following picture shows the inputs of the globus pallidus from the subthalamic and the striatum.  Pag. 13 a 21 The subthalamic is exerting a very divergent/extensive excitatory action on the internal pallidus, while the striatum has a refined action, in fact the axons (red ones in the image) contact different neurons but only one neuron is preferred, and the others are only tangentially inhibited so the action of the striatum is more refined (less extensive) with respect to that of the subthalamic on the globus pallidus internal. 3.​ The globus pallidus external is also important because it is an intermediate station receiving from striatum an inhibitory action (giving rise to the indirect pathway) and from the subthalamic nucleus an excitatory action. At the same time, the subthalamic is inhibited by the globus pallidus, so this is a sort of autogenic inhibition if the subthalamic nucleus is considered. So, the globus pallidus is inhibited by the striatum and inhibits the subthalamic; the subthalamic excites back the external pallidus. Once the subthalamic receives inhibition from pallidus external, it is less active on the external pallidus itself, increasing its ability to inhibit the subthalamic. Looking at the whole picture, the process seems more of a positive loop rather than an autogenic inhibition. The output is inhibitory on subthalamic, striatum and substantia nigra pars reticularis; so the globus pallidus external needs to go through the subthalamic but can also exert functions independently from the subthalamic, except for the pallidus internal. There is a feedback inhibition to striatum and subthalamic nucleus, and feedforward inhibition to globus pallidus internal (feedforward because it goes through the subthalamic nucleus). 4.​ The substantia nigra pars reticularis is the other side of the internal pallidus because it basically acts like the globus pallidus as an output for the system but acting on different circuits. It receives from striatum and subthalamic exactly like the internal pallidus and then sends inhibitory output on: ​ Ventrolateral and ventralanterior thalamus (but different portions with respect to internal pallidus) ​ Midbrain extrapyramidal area ​ Intralaminar nuclei ​ Superior colliculus and paralaminar part of the mediodorsal thalamus projecting to the frontal eye fields. So, the substantia nigra pars reticularis is an assistant of the pallidus internal except for ocular movement because in this case it is the only one of the two involved in the circuit. 5.​ The substantia nigra pars compacta has mainly one input, the striatum, and the output is mainly the striatum but the action of dopamine on the spiny neurons (seen before) is different because there are neurons equipped with D1 group receptors and neurons equipped with D2 group receptors. So, the effect of dopamine on the striatum depends on receptors; there are 5 different types depending on adenylate cyclase (AC) activity. 9.​ D1 and D2 group receptors There is a group of neurons equipped with:  Pag. 14 a 21 -​ D1-D5 receptors (D1 group) and in this case the effect of dopamine stimulates AC activity to produce cAMP and increases the cortical inputs on the striate -​ D2 group (D2-D3-D4), enzyme activity is inhibited and the cortical inputs on the striate are decreased. This means that if the striatum is receiving from the cortex: ​ If there is lots of dopamine -> increased effect of cortical input, because the D1 group potentiates. ​ If there is a decreased amount of dopamine -> decreased effect. D1 receptors and D2 receptors are represented on the 2 different spiny neurons originating the 2 different pathways, direct and indirect. Dopamine excites the neurons of the direct pathway and inhibits the indirect because if there is a lot of dopamine, there will be the D1 receptors potentiating the input and increasing the excitability of the neurons equipped with D1, while inhibiting the ones equipped with D2. -​ The D1 neurons are inducing the direct pathway -​ The D2 are inducing the indirect pathway So, in presence of dopamine, the direct pathway is facilitated to the indirect one, while in lack of dopamine, there will be a facilitation of the indirect on the direct. All this circuit works thanks to 2 main factors: -​ the spontaneous activity of the single structures (modulated directly by the afferents to the basal ganglia) -​ the power of dopamine on the striatum. To summarise, the cortex goes on the striatum and excites it. The striatum, with D1 group neurons, originates the direct pathway that goes on the globus pallidus, which was inhibiting the thalamus. So, by removing this inhibition, the thalamus is released. This means that cortico-striatal input has gone through the basal ganglia and has been facilitated by the fact that the D1 are conveying the information. The D2 neurons are originating the indirect pathway, in which there is the external pallidus that is inhibiting the subthalamic, which is exciting the internal pallidus. The subthalamic and the globus pallidus internal and external have spontaneous activity. Normally, this tonic activity allows tonic inhibition of the globus pallidus but, thanks to the indirect pathway, the pallidus external is being inhibited, so the inhibition on the subthalamic is released and in turn this is allowed to excite the internal pallidus. The internal pallidus is increasing its action on the thalamus and increasing the inhibition so, when the D2 are activated, the cortico-striatal input is decreased. 10.​Importance of dopamine  Pag. 15 a 21 However, knowing this, it would seem that there can be a prevalence of one pathway on the other only if there are more neurons of one type than the other, because the cortex talks to the striatum in the same way for the two spiny neurons. In fact, the type of neuron that wins is the one preferred by dopamine; it is dopamine that decides the excitation of D1 and D2 because: ​ In presence of an average amount of dopamine, the two are excited equally. ​ If dopamine increases, the direct pathway wins. ​ If dopamine decreases, D2 wins, and the indirect pathway prevails. This is why the substantia nigra pars compacta is the regulator (modulator) of the activity of the basal ganglia. If the substantia nigra increases dopamine, the striatum is more excited in the part that originates the direct pathway. When dopamine decreases, there is increase of excitation of D2, because the inhibitory activity of the enzyme is reduced, and the indirect pathway “wins”. Since the cortico-striatal fibres are mediating the way back to the cortex after the processing inside the basal ganglia, this means that dopamine modulates the signal going back to the cortex. The cortex can bypass the control by the substantia nigra and, when it happens, there is a prevalence of the indirect pathway because the entrance through the subthalamic nucleus is a clear inhibition on the system. It is a sort of independent inhibitory pathway (independent from dopamine). As mentioned earlier, the pallidus external and subthalamic have a bidirectional connection, creating a positive loop, which means an autogenic inhibition. The D1 neurons can also go and inhibit the substantia nigra, like a sort of auto-modulation that recalls the refresh by the Golgi in the cerebellum. In the image below various types of information are given: the input, the double role of dopamine, the spontaneous activity, the fact that the globus pallidus internal and the substantia nigra pars reticularis are both output structures, the difference between substantia nigra pars compacta and reticularis, the thalamus, and the cortex. The frontal eye fields are lacking because this image concentrates on the skeletomotor loop.  Pag. 16 a 21 To summarise, the direct pathway results in movement facilitation because it excites the cortex, while the indirect pathway results in movement inhibition (lack of excitation). Then, there is the hyperdirect pathway (so-called because it goes very close to the way out) going to the subthalamus directly. 11.​Parameters of movement related to neuron discharge An experiment can be done in which the task is to do a limb movement - such as a flexion. Activities of striatum, pallidus and subthalamic nucleus are recorded. It can be noticed that, while the putamen is basically silent and discharges only when something happens, the other parts were already talking a lot. 1.​ The striatum, which is the main entrance, is not talking spontaneously. It has a low spontaneous activity (0.1 to 1 Hz, basically nothing), and this is because it is the entrance and having a spontaneous activity would confuse the system, so the entrance is like a blackboard. Looking at the parameters of movement related to the putamen discharge, it is clearly related to movement, but it is not possible to find a specific parameter to which it is related. Conclusions of studies on the striatum show that it is correlated with passive and active movements but not to, for example, specific somatosensory modalities (it reacts to vibration, light touch and joint position). It has a distinct somatotopy inside and sometimes the discharge anticipates the movement onset. The correlation is rather general on movement direction and on the relevant frame of movement (onset and end of movement). It seems to be correlated with self-initiated movement and externally driven movements. So, it can be stated that it is correlated to movement, but it cannot be said exactly to which aspect of movement. Observing the oculomotor loop, the results are exactly the same. The activity is correlated to movement and muscle discharge, which means that it is delayed with respect to the cortex because in order to move the muscle voluntarily the onset needs to come from the cortex, but the putamen is delayed so it is strange: it is active during movement, but a specific correlation cannot be found.  Pag. 17 a 21 2.​ The subthalamic nucleus is tonically active but it increases activity with active movements rather than passive. It has somatotopic organisation and, differently from the striatum, the discharge always anticipates the movement onset. It has correlation with direction of movement, amplitude, and velocity but it is impossible to be more precise in the description. It has 20 Hz of spontaneous activity 3.​ The globus pallidus internal (and also the substantia nigra pars reticularis) has a high spontaneous activity of 60-80 Hz. During movement, activity can be increased or decreased depending on timing of movement. It is correlated to movement, with a distinct somatotopy: leg-arm are in the globus pallidus internal, and face-eye are in the substantia nigra pars reticularis. The discharge occurs after movement onset. There correlations are with direction, joint position, force, velocity, and preparation and, in eye movements, it is related to saccades and the direction of gaze. So, the basal ganglia are tonically inhibiting the cortex and an interaction with the direct pathway is needed to have a decrease in the activity of the globus pallidus. 4.​ The globus pallidus external has an irregular spontaneous activity between 10 and 70 Hz and it is very difficult to establish a correlation. For sure, its activity is a delayed activity with respect to the others. The correlation between its activity and the movement parameters is inconsistent, so it seems more of a modulator rather than dealing with precise aspects of movement. 5.​ The substantia nigra pars compacta has a low spontaneous activity (2 Hz) that does not code for movement, but for significant environmental stimuli. It shows no somatotopy. It is a predictor of occurrence of behavioural events (something correlated with the context). Responding to stimuli increases or decreases the release of dopamine, and the activity of dopamine changes the striatum sensitivity to cortical stimuli. This is how the dopamine can modify the response of the basal ganglia based on the behavioural context. Looking at executive functions: in a social context, when someone wants to say  Pag. 18 a 21 something, but it is inhibited because it would not be adequate, it is the dopamine that stops the cortex from doing this action. 12.​Relation between substantia nigra and reward The reward and selection of action is something that is important for insights on substantia nigra pars compacta discharge. Looking at the discharge of a monkey dopamine neuron in response to unexpected reward or a familiar reward: -​ when there is an unexpected reward, there is an initial increase of firing -​ with a familiar reward the cell basically does not react because it has learnt the association between the behaviour and the reward. Focusing on the image: -​ the monkey in the upper panel -> free reward (which means that it is received without doing anything) -> excites a lot the substantia nigra. -​ during learning of the monkey (when the monkey is being trained to do something), it can be given a reward so that it associates a reward with the correct action. At first, the monkey thinks it is a free reward, because it does not understand, -​ but then the substantia nigra associates the correct behaviour with the reward and the firing changes. The sources of dopamine projections are the substantia nigra pars compacta and the ventral tegmentum (will be seen in the lecture regarding the brainstem). 13.​Differences between basal ganglia and cerebellum Looking at the differences between basal ganglia and cerebellum: ​ Basal ganglia afferents arrive from different cortical, areas while cerebellar afferents come mainly from motor cortex ​ Basal ganglia efferents have output to all motor areas (prefrontal) and also others, while the cerebellum talks mainly with the motor ​ As regards somatosensory connections, the basal ganglia have a few connections with the brainstem, while the cerebellum has lots of connections with the spinal cord and the brainstem. The main view of the function of the basal ganglia is that the three pathways (direct, indirect and hyperdirect) are all always working, and who decides the difference between direct and indirect is dopamine. For the hyperdirect, which is an inhibiting pathway, when a movement must be performed, this shuts down the cortex at first, then the motor program starts being computed so the cortex gets excited;  Pag. 19 a 21 however, the motor program at first is very blurred, so the indirect pathway is the one that refines the motor program. The hyperdirect prepares the “blackboard”, the direct “starts drawing”, and the indirect “refines the drawing”. 14.​Deficits following basal ganglia lesions The deficits following basal ganglia lesions are either excess or deficit (hypokinetic disorders) in movement. For example, Parkinson disease produces akinesia (impaired movement initiation) or bradykinesia (reduced movements), then also increased muscle rigidity (resistance to passive displacement) and tremor at rest. This occurs because not enough dopamine is released, and the indirect pathway prevails. The hyperkinetic disorders such as Huntington or hemiballismus result in: ​ Dyskinesia (involuntary movements): o​ Athetosis: slow writing movements of extremities o​ Chorea: jerky random limb and orofacial movements o​ Ballism: violent large amplitude proximal limb movements o​ Dystonia: more sustained abnormal postures with agonist-antagonist co-contraction ​ Hypotonia (decreased muscle tone). 15.​Role of basal ganglia in cognition, mood, and non-motor behaviour The basal ganglia are also central structures in anatomical circuits or loops that are involved in modulating non-motor aspects of behaviour. There are other loops such as: ​ The prefrontal loop, that affects cognitive functions ​ The limbic loop, that involves the cingulate cortex and ventral striatum (involved in emotional states) ​ The oculomotor loop, that is involved in the control of the frontal eye fields. So, the prefrontal loop regulates initiation and termination of cognitive processes (executive function), the limbic loop emotional behaviour and motivation. The non-motor regulatory functions of the basal ganglia may be generally the same as what the basal ganglia do in regulating the initiation of movement. The prefrontal loop may regulate the initiation and termination of cognitive processes such as planning, working memory, and attention. The limbic loop may regulate emotional behaviour and motivation. The deterioration of cognitive and emotional function in both Huntington’s and Parkinson’s disease could be the result of disruption of these non-motor loops. Patients with Tourette syndrome produce inappropriate utterances and obscenities because they have the prefrontal loop that is impaired, and they express this in terms of cognitive functions because their executive functions are compromised (talking when it is not appropriate, but also with the most inappropriate words possible). They also do motor  Pag. 20 a 21 inappropriate movements such as what we call tics, so excess of activity of the basal ganglia, mainly related to the speech areas. Other psychiatric disorders, including obsessive-compulsive disorder, depression, and chronic anxiety, may also involve dysfunctions of the limbic loop. To note is that when a drug is given to a patient, such as dopamine for Parkinson’s, it is a blessing for the patient because they start moving normally, but it is also a problem because the receptors get sort of adapted to the dopamine – meaning that the response to the administration decreases progressively. Another problem is that dopamine does not act only at this level, so there can be side effects since this drug is also a neurotransmitter. 16.​Focus on homeostasis: Huntington’s chorea Huntington’s chorea/disease (HD) is a dominantly inherited disease which is passed down through families by an autosomal dominant form of inheritance. It was first described by George Huntington in 1872. HD usually causes movement, cognitive and psychiatric disorders with a wide spectrum of signs and symptoms. Which symptoms appear first varies greatly among affected people. During the course of the disease, some disorders appear to be more dominant or have a greater effect on functional ability. HD is due to slow degeneration in the basal ganglia, which eventually leads to cell death in the brain and the decrease and increase of various neurotransmitters. The symptoms of the disease are caused by a significant reduction (volume and activity) of two principal neurotransmitters (naturally occurring chemicals in the brain): acetylcholine and GABA. This, in turn, affects the activity of the neurotransmitter dopamine, which becomes hyperactive. The disorder is partly characterised by an increase in the availability of dopamine, which can cause symptoms of chorea. The portions most severely affected are caudate and putamen. The movement disorders associated with HD can include both involuntary movements and impairments in voluntary movements: ​ Involuntary jerking or writhing movements (chorea) ​ Involuntary, sustained contracture of muscles (dystonia) ​ Muscle rigidity ​ Slow, uncoordinated fine movements ​ Slow or abnormal eye movements ​ Impaired gait, posture, and balance ​ Difficulty with the physical production of speech ​ Difficulty swallowing ​ Impairments in voluntary movements rather than the involuntary movements Pag. 21 a 21