Neurobiology of Hearing 2015: Auditory thalamus

Transcription

1 Neurobiology of Hearing 2015: Auditory thalamus MGD MGV MGM Edward L. Bartlett, Purdue University, Central Auditory Processing Lab

2 Outline Review of receptive fields Introduction to the thalamus Core versus belt organization of auditory pathways Organization of the medial geniculate body (MGB) Afferents to MGB from IC and elsewhere Reciprocal connections between MGB and cortex Auditory processing in the thalamus Driver and modulator synapses in MGB Basic physiology of each MGB subdivision Burst and tonic signaling modes in thalamus

3 Receptive fields Defined as sensory features to which a neuron responds Vision: position in space/on retina, color Somatosensation: location on skin and touch type Audition: sound frequency and amplitude Lower sensory regions receptive fields are relatively constant (e.g. auditory nerve) Higher sensory regions very specific receptive fields are synthesized from simpler inputs and non sensory inputs Thalamic and cortical fields can vary based on behavioral relevance/context

4 Most neurobiologists working today were brought up to believe in a few fundamental truths: the neuron doctrine, the electrical nature of the action potential and that the thalamus is uninteresting. Glimcher and Lau 2005, from a comment in Neuron titled Rethinking the Thalamus Thalamic nuclei have historically been considered simple relays of sensory or other inputs to the cortex Historically, its main function was an arousal dependent gate; awake = gate open, asleep = gate closed Most data from visual thalamus (lateral geniculate) How is the thalamus more than a relay?

5 Basic organization of the ascending auditory system Aud. Cortex Aud. Thalamus Perception, Decision, Action IC SOC/LL CN AN Sound sound feature extraction Cochlea

6 Main thalamic functions Charon=ferryman, relay Heimdall=guardian Werewolf= transformation

7 Basic thalamic organization Cortex Cortex Thalamus MGV MGD Thalamus Adapted from Castro-Alamancos 2004

8 Auditory pathway summary: Core vs belt, parabelt Parabelt Belt Core Hackett and Kaas 2000

9 Main subdivisions of the MGB Ventral division MGV, to core,belt Myelin stain by A. Pistorio Dorsal division MGD, to belt, parabelt Medial division MGM, to core, belt, parabelt Suprageniculate (not shown) SG

10 Nissl and calcium binding proteins reveal 5 subdivisions in the marmoset; similar in rat and cat Nissl Parvalbumin Calbindin Medial Bartlett and Wang 2011 Ventral

11 Calbindin and calretinin can be used to demarcate the non primary subdivisions of auditory thalamus Lu et al. 2009

12 Human auditory thalamus Winer 1984

13 Main projection cell types of the MGB to cortex Tufted - MGV Stellate - MGD In cats and primates, about 25% of cells are local inhibitory interneurons Smith, Bartlett, and Kowalkowski 2006 Magnocellular - MGM

14 MGV tufted neuron dendrites are arranged in iso frequency lamina, receiving IC inputs tuned to different best frequencies (BF) Cetas et al. 2003

15 Afferents (inputs) to MGB from IC and elsewhere

16 MGV receives IC input from core IC central nucleus, SG/MGM/PIN receive input from belt dorsal and external IC cortex MGV injection SG/MGM injection From LeDoux et al. 1985

17 Unlike the purely auditory MGV, the SG/MGM/PIN get spinal cord input Dark cross hatching indicates overlap of spinal cord and inferior colliculus inputs MGM From LeDoux et al SG/MGM/PIN also get visual and multimodal inputs from the superior colliculus From Linke 1999

18 Function of MGB to caudate-putamen and striatum unknown (reward?) SG/MGM/PIN also go to SUBCORTICAL targets, namely the caudate-putamen, striatum and the lateral amygdala MGB input to amygdala involved in learning and memory of negative associations (e.g. fear conditioning) From LeDoux et al. 1985

19 About 1/3 of IC neurons to MGB are GABAergic Not seen in inputs to visual or somatosensory thalamus Red: to MGB Green: GABA+ Arrows indicate double labeled neurons, or GABAergic IC neurons that project to MGB Peruzzi et al. 1997

20 Large, GABAergic neurons in IC are the primary ascending inhibitory projection to MGB Excitatory IC projections ending in large terminals typically go to tufted MGV neurons (4). Excitatory IC projections ending in small terminals typically go to tufted and stellate MGV and MGD neurons (3). The small terminal excitatory projections converge with the fast GABAergic IC inhibition (1+3) Ito and Oliver 2012

21 Effects of IC short-latency inhibition on excitatory postsynaptic potentials (EPSPs) from IC inputs control 1) Reduce amplitude of excitation and probability of spiking 2) Alter timing of spiking GABA A inhibition blocked SR95531 Bartlett and Smith 1999

22 MGB thalamocortical projections and other thalamic targets Neocortex is a 6 layered structure Layer 4 is the thalamic input layers and is largest in core sensory cortices Layers 2 3 are corticocortical inputs mainly Layer 5 is the action layer for outputs Layer 6 feeds back to thalamus Nissl stain of marmoset auditory cortex DeLamothe et al. 2006

23 Cat auditory thalamocortical and corticothalamic connections MGV, core to layers 3/4 In A1 MGD/MGM, belt to layers 1,3,4,6 of A2 SG, parabelt to layers 1 and 6 Winer et al. 2005

24 MGV is the main contributor to the core pathway. Other subdivisions contribute to belt Bartlett 2013

25 MGB tone responses

26 Humans are able to discriminate sound frequency differences behaviorally, possibly much more finely than auditory nerve. What may be the neural basis? Auditory cortex neurons in awake humans showed frequency tuning that was much closer to behavioral estimates (boxed area on left). In addition to the bandwidth, a quality factor Q can be computed as CF/BW. Auditory nerve fibers in non primates typically have Q values 5 7 maximum. Left: McLaughlin et al Right: Bitterman et al. 2008

27 Frequency tuning in the MGB of awake animals is sharp and is shaped by inhibition (center surround!) Inhibition Bartlett, Sadogopan, and Wang 2011

28 Sharply tuned units in MGB are significantly sharper than those in the auditory nerve and IC Bartlett, Sadogopan, and Wang 2011.

29 Marmoset MGB neurons have tuning sharpness similar to human behavior and macaque auditory nerve A1 MGB Bartlett and Wang 2011, J. Neurophys., 106, Joris et al. 2011, PNAS, 108,

30 Neurons outside MGV often had two or more peaks in their frequency tuning curve Bartlett and Wang 2011, J. Neurophys., 105,

31 Two tone responses in the IC and cortex IC Auditory Cortex Egorova et al Kadia and Wang 2001 Lateral inhibition primarily Lateral and harmonic inhibition

32 Example of harmonic inhibition in MGB Tone 1 alone Again, MGB is not a simple relay, but actively modifies the neural stimulus representation as it passes from IC to cortex Enhanced frequency tuning and distant two tone inhibition originating in MGB both suggest a functional role for the IC inhibitory input Tone 1 frequency = 6.96 khz. Tone 1 and Tone 2 were presented at 65 db Bartlett and Wang, unpublished

33 Nearly all IC 78% neurons MGB are units monotonic. have Nearly non monotonic 75% of auditory cortex neurons are non monotonic with respect to sound level. tone responses, many strongly so Is that created in cortex or inherited from MGB? Weakly Monotonic Strongly non monotonic (29/131, 22%) (56/131, (46/131, 43%) 35%) Bartlett and Wang 2011, J. Neurophys., 105,

34 A distinction is evident between strongly non monotonic responses and weakly non monotonic responses Bartlett and Wang 2011, J. Neurophys., 105,

35 MGV, MGVM,MGAD respond well to tones and noise. MGCD often responds only to noise or is inhibited. T+,N+ T+,N T,N+ T,N Bartlett and Wang 2011, J. Neurophys., 105,

36 Preference for noise bandwidth differs between MGB subdivisions Bandwidth Index = (Rate 0.5 oct. Rate>1 oct.) / (Rate 0.5 oct. + Rate>1 oct.) Bartlett and Wang 2011, J. Neurophys., 105,

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38 Temporal cues are very important for understanding speech even when limited spectral information is available Shannon 1995 Rosen 1992 Slow envelope modulations 2 50 Hz syllables, words Periodicity Hz stress, intonation, speaker identity Temporal Fine structure > Hz, voice, speaker identity

39 Complex signals: speech and marmoset calls Marmoset vocalization: trill twitter (short range social call) Back off man, I m a scientist trill Twitter begins

40 Differences in IC excitatory input could produce differences in spectral and temporal processing Bartlett and Smith 2002

41 Temporal cues are very important for understanding speech even when limited spectral information is available Shannon 1995 Rosen 1992 Envelope modulations 2-50 Hz Periodicity Hz Fine structure >500 Hz

42 All IC neurons are well synchronized over some range

43 All marmoset in vivo experiments in the thalamus and cortex were conducted in unanesthetized animals Anesthetics substantially alter response properties in auditory thalamic and auditory cortical neurons Effects are far less dramatic in IC and lower structures Barbituate and gas anesthetics (e.g. halothane, isoflurane), at surgical anethesia concentrations, prolong GABA currents, promoting onset bursts and slow temporal responses Ketamine and nitrous oxide reduce NMDA currents, promoting transient responses and reducing integration of input spikes

44 Electrode path, sound, and an example of recording

45 Many neurons in the auditory cortex of awake marmosets produce stimulus synchronized responses Synchronized up to 50+ Hz Explicit coding of interclick interval (ICI) Lu et al. 2001

46 Many other neurons in the auditory cortex of awake marmosets are non synchronized Monotonic increases in firing rate with decreasing ICI Implicit coding of ICI with nonsynchronized spiking Lu et al. 2001

47 IC responses are synchronized. Auditory cortex responses represent complementary ranges of repetition frequency by synchrony and by firing rate. Where does this transformation of representations occur (MGB or cortex)? How do thalamic response properties compare to cortical response properties? To what extent can the MGB be called a relay of temporal response properties?

48 Transformations in the MGB Work in marmosets suggests a transformation as information passes from inferior colliculus to auditory cortex via MGB. Example diagram of click stimuli. Bartlett and Wang, 2007

49 Synchronized and non synchronized responses represent complementary ICI ranges in MGB and cortex Bartlett and Wang 2007

50 Differences in temporal coding between MGB subdivisions Bartlett and Wang 2011, J. Neurophys., 105,

51 Across the population, MGAD responses are: Short latency, high frequency synch., temporally precise Bartlett and Wang 2011, J. Neurophys., 105,

52 The Question What are the cellular mechanisms that produce the synchronized and nonsynchronized responses? Hypothesis: The synaptic plasticity of the IC inputs, in addition to the relative timing of excitatory and inhibitory inputs, shapes the output response of auditory thalamic neurons. Bartlett and Wang, 2007

53 The strength of synaptic connections are dynamic, not fixed IC paired pulse stimulation can cause depression or facilitation Bartlett and Smith 2002

54 Consequences of depression and facilitation during train stimulation IC EX/O IC IN/EX 100 ms 10 mv 100 ms 10 mv Bartlett and Smith 2002

55 Hypothesis: Population 1 is responsible for synchronized MGB responses, and population 2 is responsible for non synchronized responses. Test this with a computational model using NEURON software!

56 MGB Response TYPES Response Type Synchronized Non-synchronized Latency Short latency Long latency Synchrony High vector strength, low pass Low vector strength, nonsynchronized Rate encoding Low pass/band pass rate High pass/band pass rate Source Inherited from IC inputs Created in MGB MGB Region Generally in MGV Generally in MGD Rabang and Bartlett, 2011

57 In terms of synapse numbers, the largest projection to MGB neurons is from auditory cortex Profuse feedback projections from layer 6 of auditory cortex, ending in small terminals. Reciprocal with thalamocortical inputs but broader. Corticothalamic layer 6 axons have collaterals in the thalamic reticular nucleus. Corticothalamic function in ongoing auditory processing is still largely unknown. Corticothalamic inputs are involved in plasticity of MGB receptive fields (Jufang He, Nobuo Suga, Jun Yan) Takayanagi and Ojima2006

58 Driver vs. modulator synapses in MGB and elsewhere Mainly IC central inputs Some cortical inputs from layer 5 belt and parabelt Cortical inputs from layer 6 IC inputs to MGD/MGM? Sherman and Guillery 2011

59 Cortiothalamic projections are more diffuse than thalamocortical projections Kimura et al. 2005

60 Physiological characteristics of driver and modulator synapses Sherman and Guillery 2011

61 Individual corticothalamic synapses are weak. Co activation and strong paired pulse facilitation make them collectively quite strong. Repetitive stimulation of CT axons produces a large depolarization and repetitive spiking This is NMDA dependent Should this potential for driving repetitive spiking activity be considered modulatory? 50 Hz stimulation Bartlett and Smith 2002

62 Membrane potential can be controlled in MGB neurons by cortical feedback Bartlett and Smith 2002

63 Corticothalamic driver synapses may be part of a sensorimotor path and a strong input to nonprimary thalamus (MGD) Sherman and Guillery 2011

64 Laser uncaging of glutamate reveals pathway specific synaptics from IC to MGB Lee et al. 2010

65 Lee et al. 2010

66 So what do we consider excitatory synapses from IC shell (belt path) to MGD? IC excitatory inputs to MGD often showed paired pulse facilitation, like modulators They also are main determinants of the receptive field, like drivers. They typically require multiple inputs to generate a spiking response, like modulators. Integrators?

67 Open questions 1. How and by what mechanisms do MGB and cortical neurons respond to complex stimuli? 2. What are the separate contributions by inhibition from IC (!), thalamic reticular nucleus, and interneurons? 3. Given the profuse corticothalamic feedback, how might that additionally shape responses? 4. How is sound processed during different states of arousal and consciousness by different MGB subdivisions (MGM)?

68 Thalamic firing modes The action potentials recorded in live animals are not just abstract spike times. Rather, they are the recorded neuronal output resulting from the movements of ions through channels.

69 Low magnification view of MGB brain slice CT/TRN LGN MGB BIC Hippo. Recording pipette

70 RESPONSES TO INTRACELLULAR CURRENT INJECTION MGV/MGD SG/MGM/PIN na.2 to.2 na.4 na.4 na 100 ms 20 mv.5 na.5 na.3 na.3 na 100 ms 20 mv 100 ms 20 mv.6 na.6 na.4 na.5 na Smith, Bartlett and Kowalkowski. J Comp Neurol May;496(3):

71 Thalamic neurons have distinct voltage-dependent firing modes Tonic -58 mv Tonic, or single spike, mode is dominant for membrane potentials > 65 mv. 20 ms 20 ms Burst -83 mv For membrane potentials < 65 mv, the burst mode becomes dominant. A T type calcium channel becomes deinactivated and produces a large depolarization. Multiple high frequency action potentials (>250 Hz) are generated by the calcium depolarization. Bartlett and Smith 1999

72 Bursts contribute to synchronizing thalamocortical networks during sleep Oscillations are generated by cyclic inhibition followed by bursting in nrt and thalamic neurons Castro-Alamancos 2004 Spontaneous spindle oscillations at 3 Hz in vitro Inhibition followed by rebound burst for each oscillatory cycle Sanchez-Vives and Mccormick 1997

73 MANY MGM NEURONS LACK A REBOUND RESPONSE MGV - rebound (100%) MGM No rebound (49%) MGM rebound (44%) -.2 na, na, na, , , ms 100 ms 100 ms 20 mv 20 mv 20 mv Smith, Bartlett and Kowalkowski. J Comp Neurol May;496(3):

74 MOST (72%) MGM NEURONS HAVE BIPHASIC AHPS MGV MGM 25 ms 10 mv 25 ms 10 mv monophasic ahp biphasic ahp Smith, Bartlett and Kowalkowski. J Comp Neurol May;496(3):

75 0 mv 2 T type calcium channel kinetics 3 80 mv 1 4 1) Closed 2) Open 3) Inactivated 4) De-inactivating Chemin et al. 2002

76 Thalamic neurons have voltage dependent firing modes Firing mode alters temporal processing capabilities Tonic mode: Depolarized membrane potentials. Faithful temporal responses up to high stimulus frequencies (~50 Hz). Burst mode: Hyperpolarized membrane potentials. Can only follow up to about 8 Hz (in visual and somatosensory system) Slice recording, electrical stimulation Castro-Alamancos et al. 2002

77 The Ca ++ burst amplifies weaker inputs Sensory input from inferior colliculus (IC) Feedback input from auditory cortex (AC) Bartlett and Smith 2002

78 What have we learned? MGV to A1, core. MGD/MGM to non primary, belt Interactions between thalamus and cortex are reciprocal MGD/MGM/SG neurons receive auditory and non auditory inputs and can project subcortically (e.g. amygdala) MGB and auditory cortex receptive fields may be simple (frequency) or complex (vocalizations) MGB neurons have two distinct firing modes, tonic and burst, that influence the stimulus respresentation in thalamus and input pattern to cortical neurons What anatomical and physiological properties make auditory thalamus neurons behave like and unlike relays of sensory information?

79 The auditory thalamus: simple gate or gatekeeper? Zuul, minion of Gozor I am the gatekeeper. Are you the keymaster?

80 On to cortex